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WRES report and action plan 2023

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Workforce Race Equality Standard Annual Report 2023 1 Table of Contents Executive Summary................................................................................................................................. 3 Introduction ............................................................................................................................................ 5 WRES Data Submission 2023 .................................................................................................................. 5
Url
/Media/UHS-website-2019/Docs/About-the-Trust/Equality-reports/WRES-report-and-action-plan-2023.pdf

Tisacel -Cyclophosphamide (250)-Fludarabine (25)

Description
Chemotherapy Protocol CHIMERIC ANTIGEN RECEPTOR T-CELL (CAR-T) THERAPY DLBCL/ FL – TISACEL – FLUDARABINE (25) –
Url
/Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/Lymphoma/Tisacel-Cyclophosphamide-250-Fludarabine-25.pdf

Tisacel-Bendamustine(90)

Description
Chemotherapy Protocol CHIMERIC ANTIGEN RECEPTOR T-CELL (CAR-T) THERAPY DLBCL/ FL – TISACEL – BENDAMUSTINE (90) Regimen This regimen will only be available to prescribe at the Wessex Blood and Marrow Transplant Unit  DLBCL/ FL - Tisagenlecleucel – Bendamustine (90) Indication  CAR-T therapy with Tisacel (Tisagenlecleucel) for the treatment of adult patients with: - Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy. - Relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy. (See separate B-cell Acute Lymphoblastic Leukaemia protocol for use in Bcell ALL)  Lymphodepleting chemotherapy must be administered prior to Tisacel. This protocol includes both lymphodepletion and CAR-T administration.  For autologous use only.  This bendamustine lymphodepleting regimen may be considered with Tisacel, in preference to the Tisacel – Fludarabine (25) – Cyclophosphamide (250), if the patient has experienced a previous Grade 4 haemorrhagic cystitis with cyclophosphamide, or demonstrated a chemorefractory state to a cyclophosphamide-containing regimen administered shortly before lymphodepleting chemotherapy. Toxicity Drug Bendamustine Tisacel (tisagenlecleucel) Adverse Effect Transfusion related GVHD, gastro-intestinal disturbances, fatigue, insomnia, cardiac dysfunction, hypotension/ hypertension, hypersensitivity reactions, hypokalaemia. Cytokine release syndrome (CRS), hepatic dysfunction, renal dysfunction, cardiac dysfunction, neurologic adverse reactions immune effector cell-associated neurotoxicity syndrome (ICANS), opportunistic infections, febrile neutropenia, HBV reactivation, prolonged cytopenias, hypogammaglobulinaemia, tumour lysis syndrome (TLS), hypersensitivity reactions. The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Patients treated with bendamustine carry a lifelong risk of transfusion associated graft versus host disease (TA-GVHD). Where blood products are required, these patients must receive only irradiated blood products for life. Local blood transfusion Version 1 (June 2023) Page 1 of 12 DLBCL / FL – Tisagenlecleucel – Bendamustine (90) departments must be notified as soon as the decision to treat is made and the patient must be issued with an alert card to carry with them at all times. Symptoms of CRS or ICANS can occur weeks after infusion and therefore the patient must be issued with an alert card to carry with them at all times. Any suspected adverse reaction to a CAR-T cell infusion should be reported. Reporting forms and information can be found at – www.mhra.gov.uk/yellowcard. Consideration should also be given to reporting adverse events to the relevant manufacturer via their usual channels. Monitoring Regimen  FBC, U&Es, renal, liver and bone, CRP, coagulation screen, ferritin and LDH prior to initiating treatment and daily thereafter.  Screening for HBV, HCV and HIV must be performed before collection of cells for Tisagenlecleucel manufacture.  Echocardiogram and baseline measure of lung function must be taken prior to initiating lymphodepletion Tisacel Nearly all patients treated with Tisacel experience some degree of CRS, including life-threatening and fatal reactions. -See WBMT Policy P-G-1 and SOP P-P-78 and P-P-79 for monitoring requirements. CRS:    Symptoms: pyrexia, tiredness, cardiac failure, tachycardia, cardiac arrythmias, dyspnoea, hypoxia, capillary leak syndrome, chills, renal impairment, headache, malaise, transaminitis, nausea, diarrhoea, hypotension. Temperature, blood pressure and oxygen saturation monitored 4-hourly after Tisacel administration on Day 0 and then twice daily as directed in accordance with local procedures. This must be documented, and CRS graded on the WBMT CRS Assessment Form in the patient’s notes. ICANS:  Symptoms: seizures, somnolence, headaches, confusion, agitation, speech disorders, tremor, encephalopathy, ataxia, memory impairment, mental status changes, hallucinations, depressed level of consciousness, delirium, dysmetria.  ICE score of the patient must be assessed twice daily and documented on the WBMT ICE Assessment Form in the patient’s notes. Version 1 (June 2023) Page 2 of 12 DLBCL / FL – Tisagenlecleucel – Bendamustine (90) Dose Modifications As a cell-based therapy and based on the mechanism of action, renal and hepatic impairment is not expected to impact tisagenlecleucel expansion and cellular kinetics; hence no formal renal and hepatic impairment studies have been performed. The dose modifications listed are for haematological, liver and renal function only. Dose adjustments may be necessary for other toxicities as well. Please discuss all dose reductions / delays with the relevant consultant before prescribing if appropriate. The approach may be different depending on the clinical circumstances. The following is a general guide only. Haematological Confirm with consultant before proceeding if there are signs of possible disease relapse. Hepatic Impairment Drug Bendamustine Bilirubin (µmol/L) Less than 21 21-51 More than 51 Dose (% of original dose) 100% 70% No information Renal Impairment Drug Bendamustine Creatinine Clearance (ml/min) More than 10 10 or less Dose (% of original dose) 100% No information. Use with caution Other Prophylactic use of systemic corticosteroids is not recommended as it may interfere with the activity of the cellular therapy and therefore, they should not be administered as part of the pre-medication. However, corticosteroids may be used in the treatment of CRS or ICANS under consultant advice. Cautions with Tisacel treatment:  Unresolved serious adverse reactions (especially pulmonary reactions, cardiac reactions, or hypotension) from preceding chemotherapies.  Active uncontrolled infection or inflammatory disease.  Active GVHD. Version 1 (June 2023) Page 3 of 12 DLBCL / FL – Tisagenlecleucel – Bendamustine (90) Regimen Drug Bendamustine Dose 90 mg/m2 Days -4, -3 Tisacel (tisagenlecleucel) 1.2 x 106 – 6 x108 cells Target dose: 0 0.6 to 6 x 108 cells Route Intravenous infusion in sodium chloride 0.9% 500ml over 30-60 minutes Intravenous infusion of one or more infusion bags within 30 minutes -see below Version 1 (June 2023) Page 4 of 12 DLBCL / FL – Tisagenlecleucel – Bendamustine (90) Dose Information  Lymphodepleting regimen must only be started after availability of Tisacel is confirmed.  Bendamustine will be dose banded according to the national dose band (2.5mg/ml).  A minimum period of time must elapse between last dose of conditioning chemotherapy and CAR-T infusion, and a longer period is required for patients with renal insufficiency. This information can be found on the patient’s CAR-T cell schedule.  CAR-T administration should not occur out of core hours or over a weekend.  Tisacel has a target dose of 0.6 to 6 x 108 cells (non-weight based dosing). This is a dosing range and the dose will vary between patients. Version 1 (June 2023) Page 5 of 12 DLBCL / FL – Tisagenlecleucel – Bendamustine (90) Administration Information Tisacel  Tisacel contains genetically modified (GM) human blood cells. Exposure to Tisacel must be avoided. Procedures for handling, personal protective equipment, spills and waste disposal must be adhered to.  Tisacel cells are cryopreserved in a bag and require thawing prior to administration. -See WBMT SOP P-P-78.  One individual treatment dose comprises 1 or more infusion bags. Each infusion bag may contain either 10-30ml (50ml bag) or 30-50ml (250ml bag) cell dispersion.  The cells must be administered gravimetrically and must not be administered via a volumetric pump, as there is no data to assure cell integrity is maintained via a pump.  Administer via a Baxter non-filtered giving set (/ latex-free without a leukocyte depleting filter) primed with sodium chloride 0.9%.  The product should be administered immediately after thawing.  The infusion must be administered over a maximum of 30 minutes. The start and stop time of infusion must be documented, including any interruption.  Gently agitate the bag during infusion to prevent cell clumping.  If the volume of Tisacel to be administered is ≤20 mL, intravenous push may be used as an alternative method of administration.  All contents of the infusion bag(s) should be infused. If more than one infusion bag has been received for the treatment dose, the next bag should only be thawed after the contents of the preceding bag have been infused.  Once the full volume of Tisacel has been administered, rinse the tubing at the same rate with 10-30ml 0.9% sodium chloride solution to ensure all Tisacel is delivered. Once completed, the infusion bag(s) and giving set must be disposed of in clinical waste, in accordance with Trust policy.  If the bag is not fully administered, this must be documented, and the consultant & pharmacist notified. The manufacturer must be informed and the remaining Tisacel should be discarded in clinical waste, with their approval.  A GM spill-kit must be transported with Tisacel and available on the ward of administration. Local procedures must be followed in the event of a spill. Version 1 (June 2023) Page 6 of 12 DLBCL / FL – Tisagenlecleucel – Bendamustine (90)  Local guidelines on handling of waste of human-derived-materials must be followed in case of accidental exposure. Work surfaces and materials which have potentially been in contact with Tisacel must be decontaminated with approved disinfectants.  See WBMT SOP P-P-78, P-P-79 and Policy P-G-1 for further administration direction. Bendamustine Skin Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis have been reported in patients who received bendamustine and allopurinol simultaneously. If patients experience any skin reactions during treatment, they should be monitored closely and, in the case of any suspicion of the skin reaction evolving to a serious muco-cutaneous reaction, treatment with bendamustine should be withheld until complete resolution of the event or discontinued. Other potential causes of skin toxicity should be evaluated and suspected agents discontinued accordingly. Potassium In patients with cardiac dysfunction ensure the potassium remains above 3.5mmol/L during treatment with bendamustine. Extravasation  Bendamustine –vesicant Additional Therapy  Antiemetics - metoclopramide 10mg three times a day oral or intravenous - ondansetron 8mg twice a day oral or intravenous  Anti-infective prophylaxis as follows: - Aciclovir 400mg oral twice a day - Fluconazole 100mg once a day - Pentamidine 300mg nebuliser during lymphodepletion. To be continued every 28 days until count recovery sufficient for co-trimoxazole use at consultant advice. - Posaconazole 300mg once daily if prolonged neutropenia or previous invasive fungal infection Version 1 (June 2023) Page 7 of 12 DLBCL / FL – Tisagenlecleucel – Bendamustine (90)  Gastric protection with a proton pump inhibitor or a H2 antagonist to commence on first day on lymphodepletion until platelet count > 50 x109/L  Mouthwashes according to local or national policy on the treatment of mucositis. May include: - Nystatin 1ml four times a day - Sodium chloride 0.9% 10ml four times a day  Prior to the administration of the Tisacel - Chlorphenamine 10mg intravenous - Paracetamol 1000mg oral Pethidine 25mg intravenous can be administered under the supervision of a doctor for the treatment of rigors.  Seizure prophylaxis may be considered due to the risk of neurotoxicity associated with Tisacel or if the patient has a history of seizures. - Levetiracetam 500mg twice daily orally commencing on day 0 until day +30. - This may then be reduced to 250mg orally twice daily for one week and then stopped.  Tocilizumab must be prescribed as when required in advance of CAR-T infusion, in the event of CRS. - Tocilizumab 8mg/kg (maximum 800mg) intravenously 8-hourly if required. Maximum of four doses. - Four doses of tocilizumab must be available on the ward prior to infusion of Tisacel. Follow local procedures for administration.  Tumour lysis syndrome (TLS) prophylaxis should be prescribed according to the individual patient TLS risk and at consultant review. This must start on the day of lymphodepletion and be re-reviewed on the day of Tisacel infusion. TLS prophylaxis may include: - Allopurinol 300mg oral once a day - Rasburicase 7.5mg intravenous injection once a day Additional Information Bendamustine metabolism involves cytochrome P450 (CYP) 1A2 isoenzyme. Therefore, the potential for interaction with CYP1A2 exists. Always check for drug interactions. Version 1 (June 2023) Page 8 of 12 DLBCL / FL – Tisagenlecleucel – Bendamustine (90) References 1. Fischer K, Cramer P, Busch R et al. Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group.J.Clin.Oncol. 2011 Sep 10;29(26):3559-66 2. P-P-78 Wessex Blood and Marrow Transplant – CAR-T and IEC infusion procedure Version 2 3. P-P-79 Wessex Blood and Marrow Transplant – Immune effector cells including CAR-T cells policy Version 2.1 4. P-G-1 Wessex Blood and Marrow Transplant -Patient monitoring after CAR-T cell infusion Version 2.0 5. Pan UK Pharmacy Working Group for ATMPs -Supportive medications recommended for adults receiving licensed chimeric antigen receptor -T (CAR-T) cell therapy Version 1 May 2022 6. Pan UK Pharmacy Working Group for ATMPs -Medication restrictions for patients having CAR-T cell therapy Version 4 July 2022 7. Summary of Product Characteristics for Kymriah cells dispersion for infusion (Novartis Pharmaceuticals UK Ltd) -Last updated 6 June 2023 8. Summary of Product Characteristics for Bendamustine hydrochloride 2.5mg/ml powder for concentrate for solution for infusion (Seacross Pharmaceuticals Ltd) -Last updated 18 November 2021 9. Renal Drug Database monograph for Bendamustine -Last updated 30 October 2017 Version 1 (June 2023) Page 9 of 12 DLBCL / FL – Tisagenlecleucel – Bendamustine (90) REGIMEN SUMMARY DLBCL/ FL – TISACEL – BENDAMUSTINE (90) Other than those listed below, supportive medication for this regimen will not appear in Aria as prescribed agents. The administration instructions for each warning describe the agents that must be prescribed on the in-patient chart or general electronic prescribing system. Day – 4 1. Warning – Check supportive medication prescribed Administration instructions Please refer to the individual CAR-T schedule for full details of the required supportive medicines. 1. Antibacterials in accordance with the individual CAR-T schedule 2. Antifungals in accordance with the individual CAR-T schedule 3. Antivirals in accordance with the individual CAR-T schedule 4. Tocilizumab 8mg/kg (maximum 800mg) intravenous 8-hourly when required in the event of CRS. Maximum four doses. 5. Metoclopramide 10mg three times a day oral or intravenous 6. Ondansetron 8mg twice a day oral or intravenous 7. Nystatin mouthwash 1ml four times a day 8. Sodium chloride 0.9% mouthwash 10ml four times a day 9. Chlorphenamine 10mg intravenous when required as a premedication 10. Paracetamol 1000mg when required as a premedication oral 11. Furosemide 20mg four times a day when required for the treatment of fluid overload oral or intravenous 12. Gastric protection 13. Heparin line lock in accordance with Trust central venous access device management procedure 14. Levetiracetam 500mg twice daily oral 15. Reminders for chemotherapy administration and Tisacel. Ensure patient has been issued with Tisacel treatment alert card. 2. Warning – Check blood transfusion status Administration instructions Patients treated with bendamustine carry a lifelong risk of transfusion associated graft versus host disease. Where blood products are required these patients must receive ONLY IRRADIATED BLOOD PRODUCTS for life. Ensure transfusion departments are notified and the patient has been issued with an alert card to carry with them at all times. 3. Bendamustine 90mg/m2 intravenous infusion in 500ml sodium chloride 0.9% over 30 minutes Administration Instructions Bendamustine may be given over 30-60 minutes Day – 3 4. Bendamustine 90mg/m2 intravenous infusion in 500ml sodium chloride 0.9% over 30 minutes Administration Instructions Bendamustine may be given over 30-60 minutes Day 0 5. Chlorphenamine 10mg intravenous Administration Instructions Administer 30 minutes prior to Tisacel. Check on the in-patient system if the patient has already received a dose 6. Paracetamol 1000mg oral Administration Instructions Version 1 (June 2023) Page 10 of 12 DLBCL / FL – Tisagenlecleucel – Bendamustine (90) Administer 30 minutes prior to Tisacel. Check to ensure the patient has not already been administered paracetamol. The maximum dose is 4000mg/24 hours. 7. Tisacel (Tisagenlecleucel) 1 dose intravenous infusion Administration Instructions Prescribed dose for this patient: ……………………… The cells must be administered gravimetrically and must not be administered via a volumetric pump. Administer via a Baxter non-leukodepleting filter latex-free giving set primed with sodium chloride 0.9%. Tisacel infusion should be infused within 30 minutes of thaw completion time. Version 1 (June 2023) Page 11 of 12 DLBCL / FL – Tisagenlecleucel – Bendamustine (90) DOCUMENT CONTROL Version Date 1 June 2023 Amendment None Written By Madeleine Norbury Pharmacist Approved By Dr Rob Lown Consultant This chemotherapy protocol has been developed as part of the chemotherapy electronic prescribing project. This was and remains a collaborative project that originated from the former CSCCN. These documents have been approved on behalf of the following Trusts; University Hospital Southampton NHS Foundation Trust All actions have been taken to ensure these protocols are correct. However, no responsibility can be taken for errors which occur as a result of following these guidelines. Version 1 (June 2023) Page 12 of 12 DLBCL / FL – Tisagenlecleucel – Bendamustine (90)
Url
/Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/Lymphoma/Tisacel-Bendamustine90.pdf

Transient ischemic attack (TIA) - patient information

Description
Transient ischemic attack (TIA) Information for patients You have been given this booklet because you have been referred to the TIA
Url
/Media/UHS-website-2019/Patientinformation/Brain-and-spine/Transient-ischemic-attack-TIA-685-PIL.pdf

Enhanced recovery after oesophagogastric surgery (EROS) - patient information

Description
This leaflet explains what the enhanced recovery programme involves following oesophagogastric surgery (EROS).
Url
/Media/UHS-website-2019/Patientinformation/Surgery/Enhanced-recovery-after-oesophagogastric-surgery-EROS-1404-PIL.pdf

Carotid endarterectomy - patient information

Description
Information about having a carotid endarterectomy
Url
/Media/UHS-website-2019/Patientinformation/Cardiovascular-and-thoracic/Carotid-endarterectomy-1656-PIL.pdf

Adult hydrocephalus and shunts - patient information

Description
Hydrocephalus is a condition in which cerebrospinal fluid (CSF) builds up within the brain.
Url
/Media/UHS-website-2019/Patientinformation/Brain-and-spine/Adult-hydrocephalus-and-shunts-1520-PIL.pdf

DRC-Cyclophosphamide-Dexamethasone-Rituximab

Description
Chemotherapy Protocol LYMPHOMA CYCLOPHOSPHAMIDE - DEXAMETHASONE – RITUXIMAB (DRC) Regimen • Lymph
Url
/Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/Lymphoma/DRC-Cyclophosphamide-Dexamethasone-Rituximab.pdf

MyelomaBortezomib SC DexamethasonePabinostat 28 day

Description
Chemotherapy Protocol MULTIPLE MYELOMA BORTEZOMIB (SC)-DEXAMETHASONE-PANOBINOSTAT (28 day) Regimen • Multiple Myeloma – Bortezomib (SC)-Dexamethasone-Panobinostat (28 day) Indication • Panobinostat
Url
/Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/Myeloma/MyelomaBortezomib-SC-DexamethasonePabinostat-28-day.pdf

MyelomaBortezomib SC DexamethasonePabinostat 21day Ver1.1

Description
Chemotherapy Protocol MULTIPLE MYELOMA BORTEZOMIB (SC)-DEXAMETHASONE-PANOBINOSTAT (21 day) Regimen • Multiple Myeloma – Bortezomib (SC)-Dexamethasone-Panobinostat (21 day) Indication • Panobinostat in combination with bortezomib and dexamethasone is recommended, within its marketing authorisation, as an option for treating multiple myeloma. That is, for adult patients with relapsed and/or refractory multiple myeloma who have received at least two prior regimens including bortezomib and an immunomodulatory agent, when the company provides panobinostat with the discount agreed in the patient access scheme. • Performance status 0, 1, 2 Toxicity Drug Bortezomib Dexamethasone Panobinostat Adverse Effect GI disturbances, peripheral neuropathy, hypotension, dizziness, blurred vision, headache, musculoskeletal pain, pyrexia Weight gain, GI disturbances, hyperglycaemia, CNS disturbances, cushingoid changes, glucose intolerance QT interval prolongation, diarrhoea, nausea, vomiting, thrombocytopenia, anaemia The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Monitoring • FBC should be checked prior to each dose of bortezomib, that is on days 1 and 8. Consider before days 15 and / or 18 in patients who are 65 years or older or who have platelets less than 150x109/L. • LFTs and U&Es prior to day 1 of each cycle. • ECG prior to day 1 • Paraprotein or light chains every 3 weeks • Regular monitoring of blood glucose is considered good practice but optional Version 1.1 (Dec 2016) Page 1 of 12 Multiple Myeloma-Bortezomib (SC)-Dexamethasone-Panobinostat (21 day) • Women of childbearing potential must have a negative pregnancy test at screening and men who are sexually active with a woman of childbearing potential must agree to use barrier methods of contraception • Prior to starting treatment with panobinostat do an ECG. QTcF must be less than 480ms before initiation of treatment with panobinostat. This should be repeated on day one of cycle two, a single ECG is acceptable if no apparent QTcF prolongation is noted. In the following cycles no further ECG is required for patients with no apparent QTcF prolongation. Periodical ECGs are recommended as clinically indicated Dose Modifications The dose modifications listed are for haematological, liver and renal function and drug specific toxicities only. Dose adjustments may be necessary for other toxicities as well. In principle all dose reductions due to adverse drug reactions should not be re-escalated in subsequent cycles without consultant approval. It is also a general rule for chemotherapy that if a third dose reduction is necessary treatment should be stopped. Please discuss all dose reductions / delays with the relevant consultant before prescribing, if appropriate. The approach may be different depending on the clinical circumstances. Haematological Dose modifications for haematological toxicity in the table below are for general guidance only. Always refer to the responsible consultant as any dose reductions or delays will be dependent on clinical circumstances and treatment intent. Low counts can be a consequence of bone marrow infiltration as well as drug toxicity. Consider blood transfusion or erythropoietin if the patient is symptomatic of anaemia or has a haemoglobin of less than 8g/dL. Drug Initial dose Dose Level -1 Dose Level - 2 Action Panobinostat 20mg 15mg 10mg Discontinue Bortezomib 1.3mg/m2 1mg/m2 0.7 mg/m2 Discontinue Version 1.1 (Dec 2016) Page 2 of 12 Multiple Myeloma-Bortezomib (SC)-Dexamethasone-Panobinostat (21 day) Drug Bortezomib Neutrophils Dose Modifications 0.75 – 1x109/L If the neutrophils are less than 1 with febrile neutropenia or less than 0.5x109/L Maintain the same dose Interrupt treatment until febrile neutropenia resolves and the neutrophil count is greater than or equal to 1x109/L. If only 1 dose was omitted prior to correction to these levels, restart at same dose. If 2 or more doses were omitted consecutively, or within the same cycle, treatment should be restarted at a reduced dose Panobinostat 0.75 – 1x109/L 0.5-0.75x109/L less than 1x109/L with febrile neutropenia less than 0.5x109/L Maintain the same dose If single occurrence within cycle then maintain the same dose level. If there are two or more episodes within cycle then interrupt treatment until levels are 1x109/L or above and then restart at same dose level Interrupt treatment until febrile neutropenia resolves and the neutrophils are equal to or greater than 1x109/L then restart at reduced dose level Interrupt treatment until neutrophils are 1x109/L or greater, then restart at reduced dose level Drug Bortezomib Platelets Dose Modifications 25 – 50x109/L (grade 3) 25 – 50x109/L (grade 3 with haemorrhage) or platelets less than 25x109/L (grade 4) Maintain the same dose Interrupt treatment until platelets are equal to or greater than 75x109/L. If only 1 dose was omitted prior to correction to these levels, restart at same dose level If 2 or more doses were omitted consecutively, or within the same cycle, treatment should be restarted at a reduced dose level Version 1.1 (Dec 2016) Page 3 of 12 Multiple Myeloma-Bortezomib (SC)-Dexamethasone-Panobinostat (21 day) Panobinostat 25 – 50x109/L (grade 3) 25 – 50x109/L (grade 3 with haemorrhage) Maintain the same dose, monitor platelet counts every seven days Interrupt treatment. Monitor platelet counts at least weekly until they are equal to or greater than 50x109/L, then restart at reduced dose level less than 25x109/L (grade 4) Interrupt treatment. Monitor platelet counts at least weekly until they are equal to or greater than 50x109/L, then restart at reduced dose level Hepatic Impairment Please note that the approach may be different where abnormal liver function tests are due to disease involvement. Drug Bortezomib Bilirubin µmol/L 1.5xULN or below greater than 1.5xULN AST/ALT units/L N/A N/A Dose (% of original dose) 100% Initiate treatment at 0.7mg/m2. The dose may be escalated to 1mg/m2 or reduced to 0.5mg/m2 in subsequent cycles based on patient tolerability. Panobinostat Bilirubin 1-1.5xULN and / or any abnormal AST For the first treatment cycle start panobinostat at a reduced dose of 15mg and increase in subsequent cycles as tolerated. If this occurs during treatment then temporarily discontinue dosing until resolved to grade 2 or less or baseline and then restart treatment, reduced by one dose level Bilirubin between 1.5-3xULN and any abnormal AST For the first treatment cycle start panobinostat at a reduced dose of 10mg and increase to 15mg in subsequent cycles as tolerated. If this occurs during treatment then temporarily discontinue dosing until resolved to grade 2 or less or baseline and then restart treatment, reduced by one dose level Version 1.1 (Dec 2016) Page 4 of 12 Multiple Myeloma-Bortezomib (SC)-Dexamethasone-Panobinostat (21 day) Renal Impairment Drug Bortezomib Creatinine Clearance (ml/min) greater than 20 20 and below Dose (% of original dose) 100% Clinical decision Panobinostat No dose adjustments are necessary in those with mild to moderate renal impairment Other Dose reductions or interruptions in therapy are not necessary for those toxicities that are considered unlikely to be serious or life threatening. For example, alopecia, altered taste or nail changes. Gastrointestinal Gastrointestinal toxicity is particularly problematic with panobinostat Adverse drug reaction Diarrhoea Grade 2 despite antidiarrhoeals 3 despite antidiarrhoeals 4 despite antidiarrhoeals Panobinostat Modifications Omit dose until recovery to grade 1 or less then resume at the same dose Omit dose until recovery to grade 1 or less then resume treatment at a reduced dose Permanently discontinue Bortezomib Modifications Omit dose until recovery to grade 1 or less then resume treatment at a reduced dose level or change to once weekly Omit dose until recovery to grade 1 or less then resume treatment with the same dose on a once weekly schedule Permanently discontinue Version 1.1 (Dec 2016) Page 5 of 12 Multiple Myeloma-Bortezomib (SC)-Dexamethasone-Panobinostat (21 day) Bortezomib Neuropathic pain and/or peripheral neuropathy For patients experiencing NCI-CTC grade 1 neuropathy continue with full dose. For NCI-CTC grade 1 with pain or grade 2 neuropathy reduce the dose of bortezomib to 1mg/m2 or switch to a weekly bortezomib at the standard dose of 1.3mg/m2 For NCI-CTC grade 2 with pain or grade 3 neuropathy discontinue treatment until symptoms have resolved to NCI-CTC grade 1 or less then reinitiate bortezomib at a dose of 0.7mg/m2 For NCI-CTC grade 4 neuropathy and/or severe autonomic neuropathy discontinue bortezomib. For any other NCI-CTC grade 3 non haematological toxicity bortezomib should be discontinued until symptoms have resolve to NCI-CTC grade 1 or below. On the first occurrence treatment may be reinitiated at a dose of 1mg/m2. Following second occurrence to dose should be further reduced to 0.7mg/m2 once symptoms have resolved. If the toxicity is not resolved or if it recurs at the lowest dose, discontinuation of bortezomib must be considered unless the benefit of treatment clearly outweighs the risk. Panobinostat QTc Prolongation If a prolonged QT interval is found on ECG prior to initiation of panobinostat (QTcF greater than or equal to 480ms or above 60ms from baseline), the start of therapy should be delayed until pre-dose average QTcF has returned to less than 480 ms and abnormal serum potassium, magnesium or phosphorus values corrected. In the event of QT prolongation during treatment: • The dose should be omitted if the QTcF is greater than or equal to 480ms or above 60ms from baseline. • If the QT prolongation is resolved within 7 days, resume treatment at prior dose for initial occurrence or at reduced dose if QT prolongation is recurrent. • If QT prolongation is unresolved within 7 days, treatment should be discontinued. • If any QTcF value is above 500 ms, panobinstat should be permanently discontinued Regimen 21 day cycle for cycle 1, 2, 3, 4, 5, 6, 7, 8 Drug Bortezomib Dexamethasone Panobinostat Version 1.1 (Dec 2016) Dose 1.3mg/m2 20mg 20mg Days 1, 4, 8, 11 1, 2, 4, 5, 8, 9, 11, 12 1, 3, 5, 8, 10, 12 Administration Subcutaneous injection Oral Oral Page 6 of 12 Multiple Myeloma-Bortezomib (SC)-Dexamethasone-Panobinostat (21 day) 21 day cycle for cycles 9, 10, 11, 12, 13, 14, 15, 16 Drug Bortezomib Dexamethasone Panobinostat Dose 1.3mg/m2 20mg 20mg Days 1, 8 1, 2, 8, 9 1, 3, 5, 8, 10, 12 Administration Subcutaneous injection Oral Oral Dose Information • Bortezomib will be dose rounded to the agreed bands • At least 72 hours must elapse between bortezomib doses • Dexamethasone is available as 500mcg and 2mg tablets • Panobinostat is available as 10mg, 15mg and 20mg capsules Administration Information • Dexamethasone should be taken in the morning, with or after food • Panobinostat should be administered orally once daily on scheduled days only, at the same time each day. The capsules should be swallowed whole with water, with or without food, and they should not be opened, crushed or chewed. If a dose is missed, it can be taken up to 12 hours after the specified dose time. If vomiting occurs the patient should not take an additional dose, but should take the next usual prescribed dose. Additional Therapy • Anti-emetics As take home medication - cyclizine 50mg three times a day oral when required • Allopurinol 300mg once a day for seven days for cycle one only • Anti-infective prophylaxis with - aciclovir 400mg twice a day oral - co-trimoxazole 960mg once day on Monday, Wednesday and Friday oral • Loperamide 4mg after the first loose stool then 2mg after each loose stool thereafter to a maximum of 16mg/24hours oral • Bisphosphonates in accordance with local policies • Mouthwashes according to local or national policy on the treatment of mucositis. Version 1.1 (Dec 2016) Page 7 of 12 Multiple Myeloma-Bortezomib (SC)-Dexamethasone-Panobinostat (21 day) • Gastric protection with a proton pump inhibitor or a H2 antagonist may be considered in patients considered at high risk of GI ulceration or bleed. Additional Information • The National Patient Safety Agency alert NPSA/2008/RRR001 must be followed when prescribing, dispensing or administering oral chemotherapy. • It must be made clear to all staff, including those in the community, that this is a short course of oral chemotherapy that must not be continued. • Patients should be assessed for suitability for oral chemotherapy prior to starting treatment. • Panobinostat prolongs the QT interval. Agents that are also associated with this adverse effect should be used with caution. This includes many anti-emetics such as ondansetron, metoclopramide and domperidone Coding • Procurement – X70.8, X72.9 • Delivery – X72.4 References 1. San-Miguel JF, Hungria VTM, Yoon S-S et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicenter randomized double-blind phase 3 trial. Lancet Oncol, 2014; 15(11): 1195-1206. 2. National Institute for Health and Care Excellence. Panobinostat for treating multiple myeloma after at least two other treatments (TA 380). January 2016 DOH:London Version 1.1 (Dec 2016) Page 8 of 12 Multiple Myeloma-Bortezomib (SC)-Dexamethasone-Panobinostat (21 day) REGIMEN SUMMARY Bortezomib (SC)-Dexamethasone-Panobinostat (21 day) Cycle 1 Day 1, 4, 8, 11 1. Bortezomib 1.3mg/m2 subcutaneous injection Take Home Medicines (day 1 only) 2. Dexamethasone 20mg once a day on days 1, 2, 4, 5, 8, 9, 11, 12 oral Administration Instructions Take in the morning with or after food. Please dispense all days on day 1 of the cycle. This may be dispensed in one bottle or individual bottles according to local practice. 3. Panobinostat 20mg once a day on days 1, 3, 5, 8, 10, 12 oral Administration Instructions Take in the morning, with or without food. Please dispense all days on day 1 of the cycle. This may be dispensed in one bottle or individual bottles according to local practice. Oral chemotherapy. 4. Cyclizine 50mg up to three times a day when required oral Administration Instructions When required for the relief of nausea. Please dispense 28 tablets or nearest original pack size. 5. Aciclovir 400mg twice a day for 21 days oral Administration Instructions Please supply 21 days or an original pack if appropriate. 6. Co-trimoxazole 960mg once a day on Monday, Wednesday and Friday for 21 days oral Administration Instructions Co-trimoxazole 960mg once a day on Mondays, Wednesdays and Fridays. Please supply 21 days. This may be dispensed as 480mg twice a day on Mondays, Wednesdays and Fridays according to local practice. 7. Allopurinol 300mg once a day for 7 days oral Administration Instructions Take with or after food with plenty of water. Please supply 7 days. 8. Gastric Protection Administration Instructions The choice of gastric protection is dependent on local formulary choice and may include; - esomeprazole 20mg once a day oral - omeprazole 20mg once a day oral - lansoprazole 15mg once a day oral - pantoprazole 20mg once a day oral - rabeprazole 20mg once a day oral - cimetidine 400mg twice a day oral - famotidine 20mg once a day oral - nizatidine 150mg twice a day oral - ranitidine 150mg twice a day oral Please dispense 21 days or nearest original pack. 9. Loperamide capsules as directed Administration Instructions When required for the relief of diarrhoea. Take 4mg initially followed by 2mg after each loose stool. Maximum 16mg per day. Please supply 60 capsules or 2 original packs if appropriate. . Version 1.1 (Dec 2016) Page 9 of 12 Multiple Myeloma-Bortezomib (SC)-Dexamethasone-Panobinostat (21 day) Cycle 2, 3, 4, 5, 6, 7, 8 Day 1, 4, 8, 11 1. Bortezomib 1.3mg/m2 subcutaneous injection Take Home Medicines (day 1 only) 2. Dexamethasone 20mg once a day on days 1, 2, 4, 5, 8, 9, 11, 12 oral Administration Instructions Take in the morning with or after food. Please dispense all days on day 1 of the cycle. This may be dispensed in one bottle or individual bottles according to local practice. 3. Panobinostat 20mg once a day on days 1, 3, 5, 8, 10, 12 oral Administration Instructions Take in the morning, with or without food. Please dispense all days on day 1 of the cycle. This may be dispensed in one bottle or individual bottles according to local practice. Oral chemotherapy. 4. Cyclizine 50mg up to three times a day when required oral Administration Instructions When required for the relief of nausea. Please dispense 28 tablets or nearest original pack size. 5. Aciclovir 400mg twice a day for 21 days oral Administration Instructions Please supply 21 days or an original pack if appropriate. 6. Co-trimoxazole 960mg once a day on Monday, Wednesday and Friday for 21 days oral Administration Instructions Co-trimoxazole 960mg once a day on Mondays, Wednesdays and Fridays. Please supply 21 days. This may be dispensed as 480mg twice a day on Mondays, Wednesdays and Fridays according to local practice. 7. Gastric Protection Administration Instructions The choice of gastric protection is dependent on local formulary choice and may include; a. esomeprazole 20mg once a day oral b. omeprazole 20mg once a day oral c. lansoprazole 15mg once a day oral d. pantoprazole 20mg once a day oral e. rabeprazole 20mg once a day oral f. cimetidine 400mg twice a day oral g. famotidine 20mg once a day oral h. nizatidine 150mg twice a day oral i. ranitidine 150mg twice a day oral Please dispense 21 days or nearest original pack. Cycles 9, 10, 11, 12, 13, 14, 15, 16 Day 1, 8 1. Bortezomib 1.3mg/m2 subcutaneous injection Take Home Medicines (day 1 only) 2. Dexamethasone 20mg once a day on days 1, 2, 8, 9 oral Administration Instructions Take in the morning with or after food. Please dispense all days on day 1 of the cycle. This may be dispensed in one Version 1.1 (Dec 2016) Page 10 of 12 Multiple Myeloma-Bortezomib (SC)-Dexamethasone-Panobinostat (21 day) bottle or individual bottles according to local practice. 3. Panobinostat 20mg once a day on days 1, 3, 5, 8, 10, 12 oral Administration Instructions Take in the morning, with or without food. Please dispense all days on day 1 of the cycle. This may be dispensed in one bottle or individual bottles according to local practice. Oral chemotherapy. 4. Cyclizine 50mg up to three times a day when required oral Administration Instructions When required for the relief of nausea. Please dispense 28 tablets or nearest original pack size. 5. Aciclovir 400mg twice a day for 21 days oral Administration Instructions Please supply 21 days or an original pack if appropriate. 6. Co-trimoxazole 960mg once a day on Monday, Wednesday and Friday for 21 days oral Administration Instructions Co-trimoxazole 960mg once a day on Mondays, Wednesdays and Fridays. Please supply 21 days. This may be dispensed as 480mg twice a day on Mondays, Wednesdays and Fridays according to local practice. 7. Gastric Protection Administration Instructions The choice of gastric protection is dependent on local formulary choice and may include; a. esomeprazole 20mg once a day oral b. omeprazole 20mg once a day oral c. lansoprazole 15mg once a day oral d. pantoprazole 20mg once a day oral e. rabeprazole 20mg once a day oral f. cimetidine 400mg twice a day oral g. famotidine 20mg once a day oral h. nizatidine 150mg twice a day oral i. ranitidine 150mg twice a day oral Please dispense 21 days or nearest original pack. Version 1.1 (Dec 2016) Page 11 of 12 Multiple Myeloma-Bortezomib (SC)-Dexamethasone-Panobinostat (21 day) DOCUMENT CONTROL Version Date Amendment Written By Approved By “Oral chemotherapy” added to panobinostat admin instructions 1.1 Quantity of cyclizine to be issued Dec 2016 standardised to 28 tablets. Quantity of loperamide to be issued Rebecca Wills Pharmacist standardised to 60 capsules and admin instructions clarified. 1 Nov 2016 None Dr Deborah Wright Pharmacist Dr Deborah Wright Pharmacist Dr Mathew Jenner Consultant Haematologist Dr Helen Dignum Consultant Haematologist This chemotherapy protocol has been developed as part of the chemotherapy electronic prescribing project. This was and remains a collaborative project that originated from the former CSCCN. These documents have been approved on behalf of the following Trusts; Hampshire Hospitals NHS Foundation Trust NHS Isle of Wight Portsmouth Hospitals NHS Trust Salisbury Hospital NHS Foundation Trust University Hospital Southampton NHS Foundation Trust Western Sussex Hospitals NHS Foundation Trust All actions have been taken to ensure these protocols are correct. However, no responsibility can be taken for errors that occur as a result of following these guidelines. Version 1.1 (Dec 2016) Page 12 of 12 Multiple Myeloma-Bortezomib (SC)-Dexamethasone-Panobinostat (21 day)
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