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PHARMACY DEPARTMENT DOCUMENT Denosumab (PROLIA® ▼)subcutaneous injection Rheumatology Shared Care Guideline Title: FILENAME PHA_Medicines management_Shared Care Guidelines_Denosumab Shared Care Guideline VERSION № 3 DATE OF ISSUE 4/02/2011 REVIEW INTERVAL 2 Years AUTHORISED BY Drug and Therapeutics Committee AUTHOR Dr Shabina Sultan – Consultant Rheumatologist Dr Cornelle Parker – Consultant Endocrinologist Linda Stewart – Pharmacist Linda Sigsworth – Rheumatology Nurse Specialist EMAIL ADDRESS OF AUTHOR [email protected] COPY № 1 LOCATION OF COPIES 1. SHAREPOINT 2. PHARMACY NETWORK ASSOCIATED WORKING INSTRUCTIONS N/A LOCATION OF WORKING INSTRUCTIONS N/A TO BE VIEWED TRUST WIDE X PHARMACY ONLY DOCUMENT REVIEW HISTORY REVIEW DATE REVIEWED BY CHANGES 4.2.13 Linda Stewart 30/9/2013 Linda Stewart – Pharmacist Review date extended. Sent to consultants for consultation Consultant now recommends that the GP start the treatment rather than initiating it. Dr Sultan – Consultant Rheumatologist Drug and Therapeutics Committee 20/11/2014 Linda Stewart – Pharmacist Dr Sultan – Consultant Rheumatologist Additional cautionary information added regarding osteonecrosis of the jaw and hypocalcaemia. Area Prescribing Committee 30/9/2015 Linda Stewart – Pharmacist Dr Sultan – Consultant Rheumatologist Area Prescribing Committee 17/12/2015 Linda Stewart – Pharmacist Dr Sultan – Consultant Rheumatologist Additional cautionary information added regarding osteonecrosis of the jaw and the provision of patient reminder cards as per Drug Safety Update July 2015 Denosumab patient safety reminder card added as an appendix. Area Prescribing Committee 4/3/2016 Linda Stewart – Pharmacist Dr Sultan – Consultant Rheumatologist Drug and Therapeutics Committee Information on osteonecrosis of the external auditory canal added from MHRA drug safety update December 2015 17/12/2017 NB: ONLY SHAREPOINT VERSION OR NUMBERED COPIES IN STATED LOCATIONS ARE VALID FOR OPERATIONAL USE Denosumab (PROLIA® ▼)subcutaneous injection Rheumatology Shared Care Guideline GENERAL STATEMENTS Denosumab is suitable for patients with established osteoporosis for both primary and secondary fracture prevention who either cannot tolerate oral medication such as bisphosphonates or strontium ranelate (i.e. GI sideeffects or rash), have renal impairment precluding the use of other drugs (eGFR < 35ml/min) or are non-compliant (usually impaired mentation) or unable to travel to hospital because of poor mobility). See also NICE guidance on Denosumab. Although denosumab is ideally suited for use in primary care it is a second line drug after oral medication (bisphosphonates and/or strontium). Its use should be recommended by a secondary care physician experienced in the use of this drug with appropriate guidance on monitoring and duration of use. The treatment can then be started in primary care. The primary care physician should inform the secondary care physician if there are any problems with the use of denosumab (i.e. side effects precluding further use, further fractures after 2-3 years) so that further appropriate treatment can be recommended. The full summary of product characteristics (SPC) should be read before prescribing. PHARMACOLOGICAL Denosumab is the first in a new class of drug to treat osteoporosis. It is a human monoclonal antibody (IgG2) BUT it does not act as an SUMMARY immunosuppressive agent. It inhibits osteoclast formation, function and survival, thereby decreasing bone resorption in cortical and trabecular bone. INDICATIONS FOR THERAPY Licensed indication Treatment of osteoporosis in postmenopausal women and in men at increased risk of fractures. Denosumab significantly reduces the risk of vertebral, non vertebral and hip fractures. [It is also important to note that Denosumab is licensed for bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures.] CONTRAINDICATIONS o Hypocalcaemia (see section 4.4 of SPC). Low Vitamin D - ensure patient is vitamin D replete. Even insufficient patients may require a stat dose of high dose vitamin D3 (100,000units) to ensure vitamin D >50 Hypersensitivity to the active substance or to any of the excipients. The needle sheath contains latex so denosumab is contra-indicated in latex allergy Page: 1 of 9 Denosumab (PROLIA® ▼)subcutaneous injection Rheumatology Shared Care Guideline CAUTIONS Osteonecrosis of the jaw (ONJ) has been reported rarely in clinical studies in patients receiving denosumab at a dose of 60 mg every 6 months for osteoporosis. Known risk factors for ONJ include a diagnosis of cancer with bone lesions, concomitant therapies (e.g., chemotherapy, antiangiogenic biologics, corticosteroids, radiotherapy to head and neck), poor oral hygiene, dental extractions, and co-morbid disorders (e.g., pre-existing dental disease, anaemia, coagulopathy, infection) and previous treatment with bisphosphonates. Denosumab 60mg (osteoporosis indication) check for ONJ risk factors before starting denosumab 60mg. A dental examination and appropriate preventive dentistry are now recommended for patient with risk factors. While on treatment, these patients should avoid invasive dental procedures if possible. If dental extraction is required then refer to maxillofacial surgery. Avoid interruption in therapy. Where retreatment is recommended it should be commenced within +/- 10 days of the six month date to prevent elevated bone turnover. Before prescribing denosumab: Give patients the patient reminder card for their medicine Explain the risk of osteonecrosis of the jaw and advise on the precautions to take – advise patients to: o tell their doctor if they have any problems with their mouth or teeth before starting treatment: if they wear dentures they should make sure their dentures fit properly before starting treatment o maintain good oral hygiene and get routine dental check-ups during treatment o tell their doctor and dentist that they are receiving denosumab if they need dental treatment or surgery o tell their doctor and dentist immediately if they have any problems with their mouth or teeth during treatment ( e.g. loose teeth, pain, swelling, non-healing sores or discharge) o do not prescribe denosumab to patients with unhealed lesions from dental or oral surgery The MHRA Drug Safety Update ‘Denosumab (Xgeva, Prolia; intravenous bisphosphonates: osteonecrosis of the jaw – further measures to minimise the risk’ shows the content of the patients reminder cards. For patients who develop ONJ while on denosumab therapy, dental surgery may exacerbate the condition. If ONJ occurs during treatment with Denosumab, use clinical judgment and guide the management plan of each patient based on individual benefit/risk evaluation. Osteonecrosis of the external auditory canal o o o o The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with ear symptoms, including chronic ear infections, or in patients with suspected cholesteatoma Possible risk factors include steroid use and chemotherapy, with or without local risk factors such as infection or trauma Patients should be advised to report any ear pain, discharge from the ear, or an ear infection during bisphosphonate treatment Report any cases of osteonecrosis of the external auditory canal suspected to be associated with bisphosphonates or any other medicines, including denosumab, on a Yellow Card Page: 2 of 9 Denosumab (PROLIA® ▼)subcutaneous injection Rheumatology Shared Care Guideline CAUTIONS CONTINUED Atypical Fracture - 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. Atypical femoral fractures may occur with little or no trauma in the subtrochanteric and diaphyseal regions of the femur. The contralateral femur should be examined in denosumabtreated patients who have sustained a femoral shaft fracture, as atypical femoral fractures are often bilateral Discontinuation of denosumab treatment should be considered if an atypical femur fracture is suspected – refer urgently to orthopaedics These events occurred rarely (in ≥ 1/10,000 to < 10/10,000 patients), based on 8,928 subjects being exposed to denosumab 60 mg in bone loss studies. POTENTIAL DRUG INTERACTIONS INITIAL SCREENING STORAGE AND PRESCRIBING Nil known Hypocalcaemia must be corrected by adequate intake of calcium and vitamin D before initiating therapy. Patients with severe renal impairment (creatinine clearance < 30 ml/min) or receiving dialysis are at greater risk of developing hypocalcaemia. Clinical monitoring of calcium levels is recommended for patients predisposed to hypocalcaemia. These patients may require alfacalcidol; liaise with endocrinology or renal team re dose of calcitriol Store in a refrigerator (2°C – 8°C). Do not freeze. Keep the pre-filled syringe in the outer carton in order to protect from light. Do not shake excessively. Shelf life is 30 months. Denosumab may be stored at room temperature (up to 25°C) for up to 30 days in the original container. Once removed from the refrigerator, it must be used within this 30 day period. The recommended dose of Denosumab is 60 mg administered as a single subcutaneous injection once every 6 months into the thigh, abdomen or back of arm. Patients must be adequately supplemented with calcium and vitamin D (see section 4.4 of SPC). MONITORING Denosumab 60mg (osteoporosis indication) o Check calcium levels: o before each dose o within two weeks after initial dose in patients with risk factors for hypocalcaemia (e.g. severe renal impairment, creatinine clearance <30ml/min) o if suspected symptoms of hypocalcaemia occur Tell patients to report symptoms of hypocalcaemia to their doctor (e.g. muscle spasm, twitches, or cramps: numbness or tingling in the fingers, toes or around the mouth. Suggest annual checks of vitamin D to ensure compliance. Page: 3 of 9 Denosumab (PROLIA® ▼)subcutaneous injection Rheumatology Shared Care Guideline ADVERSE EVENTS Patients receiving Denosumab may develop skin infections (predominantly cellulitis) leading to hospitalisation (see section 4.8 of SPC). Patients should be advised to seek prompt medical attention if they develop signs or symptoms of cellulitis. Common undesirable effects observed with an incidence of 1-10% were: urinary tract infection, upper respiratory tract infection, cataract, constipation, sciatica, rash, pain in extremity. In prostate cancer patients receiving androgen deprivation therapy, cataracts and diverticulitis were reported more frequently in the Denosumab patients compared to placebo. No imbalances of either adverse event were observed in postmenopausal women with osteoporosis. The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions. Please refer to section 4.8 of the SPC for more information. RESPONSIBILITY OF THE SPECIALIST RECOMMENDING TREATMENT Summary Assess for the suitability of treatment and duration of therapy. If recommendation for treatment is made by e-consultation then it is the responsibility of the primary care physician to provide the drug information leaflet (appended to the end of this guidance). Supply GP with summary of out-patient review, as well as the instructions provided to the patient Report any adverse events to the Committee on Safety of Medicines (CSM) at the Medicines and Health Care Regulatory Agency (MHRA). Establish process for GP to seek advice or support as needed. Page: 4 of 9 Denosumab (PROLIA® ▼)subcutaneous injection Rheumatology Shared Care Guideline RESPONSIBILITY OF Summary OTHER PRESCRIBERS As with bisphosphonates, assess the patient to ensure she has good oral hygiene and use clinical judgement to determine if a dental examination is required prior to initiating therapy (see section 4.4 of product SPC if needed) Ensure practice system is set-up to recall patient after six month interval. Ensure account is set up to order denosumab and determine if it will come direct to the practice (preferred scenario, as this is more straightforward for the patient) or if the patient will need to collect their prescription from the pharmacy. If it is the latter, ensure a reminder letter is set up to be sent to patient with the relevant instructions. Prescribe and administer denosumab at six-monthly intervals. It is important that where re-treatment is recommended this is commenced within +/10 days of the six month date to prevent elevated bone turnover. Note: a protocol on how to administer the injection is available from the pharmaceutical companies if required and is appended to the end of the guidance. The primary care physician should inform the secondary care physician if there are any problems with the use of denosumab (i.e. side effects precluding further use, further fractures after 2-3 years) so that further appropriate treatment can be recommended. Report any adverse events to the Committee on Safety of Medicines (CSM) at the Medicines and Health Care Regulatory Agency (MHRA). There is currently data for the use of denosumab for up to 8 years but a review of the need for ongoing therapy should be made after 5 years. A DEXA scan may be required. PATIENT RESPONSIBILITY All patients must maintain good oral hygiene, receive routine dental check-ups, and immediately report any oral symptoms such as dental mobility, pain, or swelling to a doctor and dentist. Patients must report symptoms of hypocalcaemia to their doctor (e.g. muscle spasm, twitches, or cramps: numbness or tingling in the fingers, toes or around the mouth. CONTACTS A patient information leaflet has been issued to your patient. If any problems occur please contact relevant specialist: Consultant Endocrinologist: 01535 294388 For Rheumatology Patients ONLY: Consultant Rheumatologists secretary: Rheumatology Nurse Specialist: Rheumatology Helpline: Pharmacy (for all patients): 01535 292067 01535 292084 01535 292084 01535 293503 Access to shared care guidelines is available via the internet at Airedale NHS Trust at: http://www.airedale-trustformulary.nhs.uk/default.asp Page: 5 of 9 Denosumab (PROLIA® ▼)subcutaneous injection Rheumatology Shared Care Guideline Appendix 1 Denosumab Patient Information Leaflet for treatment of post-menopausal osteoporosis Page: 6 of 9 Denosumab (PROLIA® ▼)subcutaneous injection Rheumatology Shared Care Guideline Page: 7 of 9 Denosumab (PROLIA® ▼)subcutaneous injection Rheumatology Shared Care Guideline Appendix 2: Support Documents for Healthcare Professionals (Available from Amgen & GlaxoSmithKline) Page: 8 of 9 Denosumab (PROLIA® ▼)subcutaneous injection Rheumatology Shared Care Guideline Page: 9 of 9