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RGDP-Cisplatin-Dexamethasone-Gemcitabine-Rituximab

Description: Chemotherapy Protocol LYMPHOMA CISPLATIN-DEXAMETHASONE-GEMCITABINE-RITUXIMAB (RGDP) Regimen • Lymphoma – RGDP-Cisplatin-Dexamethasone-Gemcitabine-Rituximab Indication
Url: /Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/Lymphoma/RGDP-Cisplatin-Dexamethasone-Gemcitabine-Rituximab.pdf

RCHOP(21)-Cyclophosphamide-Doxorubicin-Prednisolone-Rituximab-Vincristine (21) Ver 1.2

Description: Chemotherapy Protocol LYMPHOMA CYCLOPHOSPHAMIDE-DOXORUBICIN-PREDNISOLONE-RITUXIMAB-VINCRISTINE (21) (RCHOP 21) There are multiple versions of this protocol in use. Please ensure you have the correct protocol for the relevant diagnosis. Regimen Lymphoma – RCHOP(21)-Cyclophosphamide-Doxorubicin-Prednisolone-RituximabVincristine (21) Indication CD20 positive Non-Hodgkin’s Lymphoma Toxicity Drug Adverse Effect Cyclophosphamide Dysuria, haemorrhagic cystitis (rare), taste disturbances Doxorubicin Prednisolone Rituxumab Vincristine Cardiomyopathy, alopecia, urinary discolouration (red), Weight gain, gastro-intestinal disturbances, hyperglycaemia, CNS disturbances, cushingoid changes, glucose intolerance Severe cytokine release syndrome, increased incidence of infective complications, progressive multifocal leukoencephalopathy Peripheral neuropathy, constipation, jaw pain The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Monitoring Drugs FBC, LFTs and U&Es prior to day one of treatment Check hepatitis B status before starting rituximab Ensure adequate cardiac function before starting therapy. Baseline LVEF should be measured in patients with a history of cardiac problems, cardiac risk factors or in the elderly. Discontinue doxorubicin if cardiac failure develops Version 1.2 (Jan 2015) Page 1 of 11 Lymphoma-RCHOP(21)-Cyclophosphamide-Doxorubicin-Prednisolone-Rituximab-Vincristine (21) Dose Modifications The dose modifications listed are for haematological, liver and renal function and limited drug specific toxicities. 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 if patient symptomatic of anaemia or has a haemoglobin of less than 8g/dL. Dose modifications based on haematological parameters apply to cyclophosphamide and doxorubicin only Neutrophils (x109/L) Less than 1 on proposed day 1 of cycle Grade 4 neutropenia or any febrile neutropenia following any cycle Grade 4 neutropenia leading to infection despite G-CSF support Grade 4 neutropenia recurs despite 50% dose reduction in cyclophosphamide and doxorubicin Platelets (x109/L) Less than 100 on proposed day 1 of cycle Grade 4 thrombocytopenia following any cycle Grade 4 thrombocytopenia recurs despite 50% dose reduction in cyclophosphamide and doxorubicin Dose Modifications (cyclophosphamide and doxorubicin) Delay therapy until neutrophils are greater than or equal to 1x109/L Consider G-CSF as secondary prophylaxis. Reconsider treatment options if not recovered after 14 days. Give G-CSF with all subsequent cycles Reduce dose of cyclophosphamide and doxorubicin by 50% for all subsequent cycles Stop treatment Dose Modifications (cyclophosphamide and doxorubicin) Delay therapy until platelets are greater or equal to 100x109/L Reconsider treatment options if not recovered after 14 days. Reduce dose of cyclophosphamide and doxorubicin by 50% for all subsequent cycles Stop treatment Version 1.2 (Jan 2015) Page 2 of 11 Lymphoma-RCHOP(21)-Cyclophosphamide-Doxorubicin-Prednisolone-Rituximab-Vincristine (21) Hepatic Impairment Please note that the approach may be different where abnormal liver function tests are due to disease involvement. Drug Cyclophosphamide Bilirubin (μmol/L) AST/ALT (units/L) Dose (%of original dose) Evidence suggest dose modification not necessary. Doxorubicin less than *30 *30-50 and and/or 51-85 more than 85 2-3xULN More than 3xULN N/A N/A 75% 50% 25% omit Rituximab N/A N/A No dose adjustment needed *30-51 or 60-180 50% Vincristine more than 51 and normal 50% more than 51 and more than 180 omit * Lower limit reflects local practice and may differ from published sources. Renal Impairment Drug Cyclophosphamide** Creatinine Clearance (ml/min) more than 20 10-20 less than 10 Dose (% of original dose) 100% 75% 50% Doxorubicin less than 10 Consider dose reduction in severe renal failure Rituximab N/A No dose adjustment needed Vincristine N/A No dose adjustment needed **Consider mesna in patients with pre-existing bladder disorders. Give an oral dose of 40% of the cyclophosphamide dose (rounded upwards to the nearest 400mg) at 0, 2 and 6 hours after the administration of the cyclophosphamide. Version 1.2 (Jan 2015) Page 3 of 11 Lymphoma-RCHOP(21)-Cyclophosphamide-Doxorubicin-Prednisolone-Rituximab-Vincristine (21) 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. Doxorubicin Discontinue doxorubicin if cardiac failure develops Rituximab Infusion related adverse reactions have been observed in 10% of patients treated with rituximab. Rituximab administration is associated with the onset of cytokine release syndrome. This condition is characterised by severe dyspnoea, often accompanied by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. It may be associated with some features of tumour lysis syndrome such as hyperuricaemia, hyperkalaemia, hypocalcaemia, acute renal failure, elevated lactate dehydrogenase (LDH) and can lead to acute respiratory failure and death. This effect on the lungs may be accompanied by events such as pulmonary interstitial infiltration or oedema, visible on a chest x-ray. Cytokine release syndrome frequently occurs within one or two hours of initiating the first infusion. Hypersensitivity reactions, including anaphylaxis, have been reported following the intravenous administration of proteins. In contrast to cytokine release syndrome, true hypersensitivity reactions typically occur within minutes of starting the infusion. Medicinal products for the treatment of allergic reactions should be available for immediate use in the event of hypersensitivity developing during the administration of rituximab. Use of rituximab maybe associated with an increased risk of progressive multifocal leukoencephalopathy (PML). Patients must be monitored at regular intervals for any new or worsening neurological, cognitive or psychiatric symptoms that may be suggestive of PML. If PML is suspected, further dosing must be suspended until PML has been excluded. If PML is confirmed the rituximab must be permanently discontinued. The presence of a viral upper respiratory tract infection at the time of treatment may increase the risk of rituximab associated hepatotoxicity. Patients should be assessed for any cold or flu-like symptoms prior to treatment Vincristine Reduce the vincristine dose to 1mg if a NCI-CTC grade 2 motor or grade 3 sensory neurological toxicity occurs. For higher toxicity grades or if toxicity increases despite dose reduction stop the vincristine. Version 1.2 (Jan 2015) Page 4 of 11 Lymphoma-RCHOP(21)-Cyclophosphamide-Doxorubicin-Prednisolone-Rituximab-Vincristine (21) Regimen 21 day cycle for 6 cycles Drug Cyclophosphamide Dose 750mg/m2 Days Administration 1 Intravenous bolus over 10 minutes Doxorubicin Rituximab Vincristine Prednisolone 50mg/m2 375mg/m2 1.4mg/m2 (max 2mg) 100mg 1 Intravenous bolus over 10 minutes 1 1 1, 2, 3, 4, 5 Intravenous infusion in 500ml sodium chloride 0.9% Intravenous bolus in 50ml sodium chloride 0.9% over 10 minutes Oral Consider initial dose reduction in patients over 70 years of age. Doses may be escalated up to full dose on subsequent cycles according to tolerability. Dose Information Cyclophosphamide will be dose banded according to the CSCCN agreed bands Doxorubicin will be dose banded according to the CSCCN agreed bands The maximum lifetime cumulative dose of doxorubicin is 450mg/m². However prior radiotherapy to mediastinal/pericardial area should receive a lifetime cumulative doxorubicin dose of no more than 400mg/m² Rituximab will be dose rounded to the nearest 100mg (up if half way) Vincristine dose will be rounded to the nearest 0.1mg (up if halfway) The maximum dose of vincristine is 2mg Version 1.2 (Jan 2015) Page 5 of 11 Lymphoma-RCHOP(21)-Cyclophosphamide-Doxorubicin-Prednisolone-Rituximab-Vincristine (21) Administration Information Extravasation Cyclophosphamide – neutral Doxorubicin – vesicant Rituximab - neutral Vincristine - vesicant Other Prednisolone should be taken in the morning with or after food. Administration of prednisolone begins on the morning of chemotherapy. The rate of administration of rituximab varies. Please refer to the rituximab administration guidelines. Additional Therapy Antiemetics 15-30 minutes prior to chemotherapy - ondansetron 8mg oral or intravenous As take home medication - metoclopramide 10mg three times a day when required oral - ondansetron 8mg twice a day for 3 days oral Rituximab pre-medication 30 minutes prior to rituximab - chlorphenamine 10mg intravenous - paracetamol 1000mg oral On the morning of treatment - prednisolone 100mg oral to be self administered by the patient on the morning of treatment and for four days after rituximab treatment (this is part of the chemotherapy schedule as well as rituximab pre-medication) Version 1.2 (Jan 2015) Page 6 of 11 Lymphoma-RCHOP(21)-Cyclophosphamide-Doxorubicin-Prednisolone-Rituximab-Vincristine (21) Rituximab infusion reactions - hydrocortisone 100mg intravenous when required for rituximab infusion related reactions - salbutamol 2.5mg nebule when required for rituximab related bronchospasm - consider pethidine 25-50mg intravenous for rituximab related rigors that fail to respond to steroids. Allopurinol 300mg once a day oral for the first cycle only Consider anti-infective prophylaxis in high risk patients, including: - aciclovir 400mg twice a day oral - co-trimoxazole 960mg once a day oral on Monday, Wednesday and Friday only Mouthwashes according to local or national policy on the treatment of mucositis 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 report NPSA/2008/RRR04 must be followed in relation to intravenous administration of vinca alkaloids. Coding (OPCS 4.6) Procurement – X71.4 Delivery – X72.2 References 1.Coiffier B, Lepage E, Briere J et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large B cell lymphoma. N Engl J Med 2002; 346: 235-242. 2.NICE guidance - TA65 Non-Hodgkin’s Lymphoma - rituximab. September 2003 3.NICE guidance – TA137 Lymphoma (follicular non-Hodgkin’s) rituximab. February 2008 4.NICE guidance – TA243 Rituximab for the first-line treatment of stage III-IV follicular lymphoma. January 2012 5.Pfreundschuh M, Trümper L, Österborg A et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 2006; 7: 379-91. Version 1.2 (Jan 2015) Page 7 of 11 Lymphoma-RCHOP(21)-Cyclophosphamide-Doxorubicin-Prednisolone-Rituximab-Vincristine (21) REGIMEN SUMMARY RCHOP(21)-Cyclophosphamide-Doxorubicin-Prednisolone-Rituximab-Vincristine (21) Cycle 1 1. Warning – Check patient has taken the prednisolone dose* 2. Chlorphenamine 10mg intravenous 3. Paracetamol 1000mg oral 4. Rituximab 375mg/m2 intravenous infusion in 500ml sodium chloride 0.9% as per the rituximab administration guidelines 5. Ondansetron 8mg oral or intravenous injection 6. Doxorubicin 50mg/m2 intravenous bolus over 10 minutes 7. Vincristine 1.4mg/m2 (max 2mg) intravenous bolus in 50ml sodium chloride 0.9% over 10 minutes 8. Cyclophosphamide 750mg/m2 intravenous bolus over 10 minutes 9. Hydrocortisone 100mg intravenous once only when required for the relief of rituximab infusion related reactions 10. Salbutamol 2.5mg nebule once only when required for the relief of rituximab related bronchospasm Take Home Medicines 11. Prednisolone 100mg once a day on the morning of the next treatment ** 12. Prednisolone 100mg once a day for 4 days oral (starting on day 2)** 13. Metoclopramide 10mg three times a day when required oral 14. Ondansetron 8mg twice a day for 3 days oral starting on the evening of day one of treatment 15. Allopurinol 300mg once a day oral for 21 days Version 1.2 (Jan 2015) Page 8 of 11 Lymphoma-RCHOP(21)-Cyclophosphamide-Doxorubicin-Prednisolone-Rituximab-Vincristine (21) Cycles 2, 3, 4 and 5 1. Warning – Check patient has taken the prednisolone dose* 2. Chlorphenamine 10mg intravenous 3. Paracetamol 1000mg oral 4. Rituximab 375mg/m2 intravenous infusion in 500ml sodium chloride 0.9% as per the rituximab administration guidelines 5. Ondansetron 8mg oral or intravenous injection 6. Doxorubicin 50mg/m2 intravenous bolus over 10 minutes 7. Vincristine 1.4mg/m2 (max 2mg) intravenous bolus in 50ml sodium chloride 0.9% over 10 minutes 8. Cyclophosphamide 750mg/m2 intravenous bolus over 10 minutes 9. Hydrocortisone 100mg intravenous once only when required for the relief of rituximab infusion related reactions 10. Salbutamol 2.5mg nebule once only when required for the relief of rituximab related bronchospasm Take Home Medicines 11. Prednisolone 100mg once a day on the morning of the next treatment** 12. Prednisolone 100mg once a day for 4 days oral (starting on day 2)** 13. Metoclopramide 10mg three times a day when required oral 14. Ondansetron 8mg twice a day for 3 days oral starting on the evening of day one of treatment Cycle 6 1. Warning – Check patient has taken the prednisolone dose* 2. Chlorphenamine 10mg intravenous 3. Paracetamol 1000mg oral 4. Rituximab 375mg/m2 intravenous infusion in 500ml sodium chloride 0.9% as per the rituximab administration guidelines 5. Ondansetron 8mg oral or intravenous injection 6. Doxorubicin 50mg/m2 intravenous bolus over 10 minutes Version 1.2 (Jan 2015) Page 9 of 11 Lymphoma-RCHOP(21)-Cyclophosphamide-Doxorubicin-Prednisolone-Rituximab-Vincristine (21) 7. Vincristine 1.4mg/m2 (max 2mg) intravenous bolus in 50ml sodium chloride 0.9% over 10 minutes 8. Cyclophosphamide 750mg/m2 intravenous bolus over 10 minutes 9. Hydrocortisone 100mg intravenous once only when required for the relief of rituximab infusion related reactions 10. Salbutamol 2.5mg nebule once only when required for the relief of rituximab related bronchospasm Take Home Medicines 11. Prednisolone 100mg once a day for 4 days oral (starting on day 2) 12. Metoclopramide 10mg three times a day when required oral 13. Ondansetron 8mg twice a day for 3 days oral starting on the evening of day one of treatment Administration information * Please check the patient has taken prednisolone 100mg oral on the morning of rituximab administration. On occasions where individuals attend for treatment and have forgotten to take the prednisolone dose please administer prednisolone 100mg oral 30 minutes prior to rituximab administration. **The prednisolone may be dispensed as a single supply in one container or as two containers depending on local preference Version 1.2 (Jan 2015) Page 10 of 11 Lymphoma-RCHOP(21)-Cyclophosphamide-Doxorubicin-Prednisolone-Rituximab-Vincristine (21) DOCUMENT CONTROL Version Date Amendment Written By Approved By Header changed Toxicities removed Hepatic & renal tables updated Metoclopramide dose changed to 10mg Donna Kimber 1.2 Jan 2015 Bolus removed from intravenous Pharmacy bolus throughout text Technician Mucositis recommendation changed Disclaimer added Document control reordered “In patients over 70 years of age consider using vincristine 1mg. Where 1.1 July 2012 appropriate dose reduction of other agents may be considered at cycle one” changed to “Consider initial dose Rebecca Wills Pharmacist reduction in patients over 70 years of age.” 1 April 2012 None Rebecca Wills Pharmacist Dr Debbie Wright Pharmacist Rebecca Wills Pharmacist Dr Debbie Wright Pharmacist Dr Andrew Davies Consultant Medical Oncologist Dr Alison Milne 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 Hospitals 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 which occur as a result of following these guidelines. Version 1.2 (Jan 2015) Page 11 of 11 Lymphoma-RCHOP(21)-Cyclophosphamide-Doxorubicin-Prednisolone-Rituximab-Vincristine (21)
Url: /Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/Lymphoma/RCHOP21-Cyclophosphamide-Doxorubicin-Prednisolone-Rituximab-Vincristine-21-Ver-1.2.pdf

RCEOP-Cyclophosphamide-Etoposide-Prednisolone-Rituximab-Vincristine Ver 1.2

Description: Chemotherapy Protocol LYMPHOMA CYCLOPHOSPHAMIDE-ETOPOSIDE-PREDNISOLONE-RITUXIMAB-VINCRISTINE Regimen (RCEOP) Lymphoma – RCEOP-Cyclophosphamide-Etoposide-Prednisolone-RituximabVincristine Indication Non Hodgkin’s Lymphoma where the use of an anthracycline based regimen is contra-indicated Toxicity Drug Adverse Effect Cyclophosphamide Dysuria, haemorrhagic cystitis (rare), taste disturbances Etoposide Hypotension on rapid infusion, alopecia, hyperbilirubinaemia Vincristine Rituxumab Prednisolone Peripheral neuropathy, constipation, jaw pain Severe cytokine release syndrome, increased incidence of infective complications, progressive multifocal leukoencephalopathy Weight gain, gastro-intestinal disturbances, hyperglycaemia, CNS disturbances, cushingoid changes, glucose intolerance The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Monitoring Drugs FBC, LFTs and U&Es prior to day one of treatment Albumin prior to each cycle Check hepatitis B status before starting treatment with rituximab Dose Modifications The dose modifications listed are for haematological, liver and renal function and some 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. Version 1.2 (Jan 2015) Page 1 of 11 Lymphoma- RCEOP-Cyclophosphamide-Etoposide-Prednisolone-Rituximab-Vincristine 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 if patient symptomatic of anaemia or has a haemoglobin of less than 8g/dL. Dose modifications based on haematological parameters apply to cyclophosphamide and etoposide only Neutrophils (x109/L) 1 or greater Dose Modifications (cyclophosphamide and etoposide) 100% 1st Occurrence If the intent is curative and growth factor prophylaxis has not been previously given administer 100% of the dose plus prophylactic growth factors. 0.5 – 0.9 Alternatively delay until the neutrophils are 1x109/L or above and then give 75% of the original dose less than 0.5 or febrile neutropenia Platelets (x109/L) 75 or above 50 – 74 Less than 50 or signs of active haemorrhage 2nd Occurrence Delay until neutrophils are 1x109/L or above and then give 50% of the original dose plus prophylactic growth factors 1st Occurrence Delay until the neutrophils are 1x109/L or above and then give 75% of the original dose plus prophylactic growth factors 2nd Occurrence Delay until the neutrophils are 1x109/L or above and then give 50% of the original dose plus prophylactic growth factors Dose Modifications (cyclophosphamide and etoposide) 100% 1st Occurrence Give 75% of the dose 2nd Occurrence Give 50% of the dose 1st Occurence Delay until the platelets are 75 or above then give 75% of the original dose 2nd Occurrence Delay until the platelets are 75 or above then give 50% of the original dose Version 1.2 (Jan 2015) Page 2 of 11 Lymphoma- RCEOP-Cyclophosphamide-Etoposide-Prednisolone-Rituximab-Vincristine Hepatic Impairment Please note that the approach may be different where abnormal liver function tests are due to disease involvement. Drug Cyclophosphamide Bilirubin (μmol/L) AST/ALT (units/L) Dose (%of original dose) Evidence suggests no dose adjustment needed. Etoposide *30-51 Or more than 51 Or 60-180 More than180 Consider dose reducing to 50% Clinical decision Rituximab N/A N/A No dose adjustment needed *30-51 Or 60-180 50% Vincristine more than 51 And normal 50% more than 51 And more than 180 omit * The lower limit reflects local practice and may differ from published sources. Renal Impairment Drug Cyclophosphamide* Creatinine Clearance (ml/min) more than 20 10-20 less than10 Dose (% of original dose) 100% 75% 50% Etoposide more than 50 15-50 Less than15 100% 75% 50% Rituximab N/A No dose adjustment needed Vincristine N/A No dose adjustment needed *Consider mesna in patients with pre-existing bladder disorders. Give an oral dose of 40% of the cyclophosphamide dose (rounded upwards to the nearest 400mg) at 0, 2 and 6 hours after the administration of the cyclophosphamide. Version 1.2 (Jan 2015) Page 3 of 11 Lymphoma- RCEOP-Cyclophosphamide-Etoposide-Prednisolone-Rituximab-Vincristine 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. Etoposide Where significant reductions in albumin levels occur consider reducing the dose of etoposide. Rituximab Infusion related adverse reactions have been observed in 10% of patients treated with rituximab. Rituximab administration is associated with the onset of cytokine release syndrome. This condition is characterised by severe dyspnoea, often accompanied by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. It may be associated with some features of tumour lysis syndrome such as hyperuricaemia, hyperkalaemia, hypocalcaemia, acute renal failure, elevated lactate dehydrogenase (LDH) and can lead to acute respiratory failure and death. This effect on the lungs may be accompanied by events such as pulmonary interstitial infiltration or oedema, visible on a chest x-ray. Cytokine release syndrome frequently occurs within one or two hours of initiating the first infusion. Hypersensitivity reactions, including anaphylaxis, have been reported following the intravenous administration of proteins. In contrast to cytokine release syndrome, true hypersensitivity reactions typically occur within minutes of starting the infusion. Medicinal products for the treatment of allergic reactions should be available for immediate use in the event of hypersensitivity developing during the administration of rituximab. Use of rituximab maybe associated with an increased risk of progressive multifocal leukoencephalopathy (PML). Patients must be monitored at regular intervals for any new or worsening neurological, cognitive or psychiatric symptoms that may be suggestive of PML. If PML is suspected, further dosing must be suspended until PML has been excluded. If PML is confirmed the rituximab must be permanently discontinued. The presence of a viral upper respiratory tract infection at the time of treatment may increase the risk of rituximab associated hepatotoxicity. Patients should be assessed for any cold or flu-like symptoms prior to treatment. Vincristine Reduce the vincristine dose to 1mg if a NCI-CTC grade 2 motor or grade 3 sensory neurological toxicity occurs. For higher toxicity grades or if toxicity increases despite dose reduction stop the vincristine. Version 1.2 (Jan 2015) Page 4 of 11 Lymphoma- RCEOP-Cyclophosphamide-Etoposide-Prednisolone-Rituximab-Vincristine Regimen 21 day cycle for 6 cycles Drug Cyclophosphamide Etoposide Rituximab Vincristine Etoposide Prednisolone Dose 750mg/m2 150mg/m2 375mg/m2 1.4mg/m2 (max 2mg) 100mg/m2 100mg Days Administration 1 Intravenous bolus over 10 minutes Intravenous infusion in 1000ml 1 sodium chloride 0.9% over 60 minutes 1 Intravenous infusion in 500ml sodium chloride 0.9% 1 Intravenous bolus in 50ml sodium chloride 0.9% over 10 minutes 2 and 3 Oral 1, 2, 3, 4, 5 Oral Consider initial dose reduction in patients over 70 years of age. Doses may be escalated up to full dose on subsequent cycles according to tolerability. Dose Information Cyclophosphamide will be dose banded according to the CSCCN agreed bands Etoposide (intravenous) will be dose banded according to the CSCCN agreed bands Etoposide (oral) is available as 50mg and 100mg capsules. All doses will be rounded to the nearest 50mg (up if halfway) Rituximab will be rounded banded to the nearest 100mg (up if halfway) Vincristine dose will be rounded to the nearest 0.1mg (up if halfway) The maximum dose of vincristine is 2mg Administration Information Extravasation Cyclophosphamide – neutral Etoposide – irritant Rituximab - neutral Vincristine - vesicant Version 1.2 (Jan 2015) Page 5 of 11 Lymphoma- RCEOP-Cyclophosphamide-Etoposide-Prednisolone-Rituximab-Vincristine Other Etoposide (oral) should be taken an hour before food or on an empty stomach Prednisolone should be taken in the morning with or after food. Administration of prednisolone begins on the morning of chemotherapy. The rate of administration of rituximab varies. Please refer to the rituximab administration guidelines. Additional Therapy Antiemetics 15-30 minutes prior to chemotherapy - ondansetron 8mg oral or intravenous As take home medication - metoclopramide 10mg three times a day when required oral - ondansetron 8mg twice a day for 3 days oral Rituximab pre-medication 30 minutes prior to rituximab - chlorphenamine 10mg intravenous - paracetamol 1000mg oral On the morning of treatment - prednisolone 100mg oral to be self administered by the patient on the morning of treatment and for four days after rituximab treatment (this is part of the chemotherapy schedule as well as rituximab pre-medication) Version 1.2 (Jan 2015) Page 6 of 11 Lymphoma- RCEOP-Cyclophosphamide-Etoposide-Prednisolone-Rituximab-Vincristine Rituximab infusion reactions - hydrocortisone 100mg intravenous when required for rituximab infusion related reactions - salbutamol 2.5mg nebule when required for rituximab related bronchospasm - consider pethidine 25-50mg intravenous for rituximab related rigors that fail to respond to steroids. Allopurinol 300mg once a day oral for the first cycle only Consider anti-infective prophylaxis in high risk patients, including: - aciclovir 400mg twice a day oral - co-trimoxazole 960mg once a day oral on Monday, Wednesday and Friday only oral Mouthwashes according to local or national policy on the treatment of mucositis 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. The National Patient Safety Agency report NPSA/2008/RRR04 must be followed in relation to intravenous administration of vinca alkaloids. Coding (OPCS 4.6) Procurement – X71.3 Delivery – X72.1 Version 1.2 (Jan 2015) Page 7 of 11 Lymphoma- RCEOP-Cyclophosphamide-Etoposide-Prednisolone-Rituximab-Vincristine REGIMEN SUMMARY RCEOP-Cyclophosphamide-Etoposide-Prednisolone-Rituximab-Vincristine Cycle 1 1. Warning – Check patient has taken the prednisolone dose* 2. Chlorphenamine 10mg intravenous 3. Paracetamol 1000mg oral 4. Rituximab 375mg/m2 intravenous infusion in 500ml sodium chloride 0.9% as per the rituximab administration guidelines 5. Ondansetron 8mg oral or intravenous injection 6. Vincristine 1.4mg/m2 (max 2mg) intravenous bolus in 50ml sodium chloride 0.9% over 10 minutes 7. Etoposide 150mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes 8. Cyclophosphamide 750mg/m2 intravenous bolus over 10 minutes 9. Hydrocortisone 100mg intravenous once only when required for the relief of rituximab infusion related reactions 10. Salbutamol 2.5mg nebule once only when required for the relief of rituximab related bronchospasm Take Home Medicines 11. Etoposide 100mg/m2 once a day for 2 days oral (starting on day 2) 12. Prednisolone 100mg once a day on the morning of the next treatment** 13. Prednisolone 100mg once a day for 4 days oral (starting on day 2)** 14. Metoclopramide 10mg three times a day when required oral 15. Ondansetron 8mg twice a day for 3 days oral starting on the evening of day one of treatment 16. Allopurinol 300mg once a day oral for 21 days Cycles 2, 3, 4 and 5 1. Warning – Check patient has taken the prednisolone dose* 2. Chlorphenamine 10mg intravenous Version 1.2 (Jan 2015) Page 8 of 11 Lymphoma- RCEOP-Cyclophosphamide-Etoposide-Prednisolone-Rituximab-Vincristine 3. Paracetamol 1000mg oral 4. Rituximab 375mg/m2 intravenous infusion in 500ml sodium chloride 0.9% as per the rituximab administration guidelines 5. Ondansetron 8mg oral or intravenous injection 6. Vincristine 1.4mg/m2 (max 2mg) intravenous bolus in 50ml sodium chloride 0.9% over 10 minutes 7. Etoposide 150mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes 8. Cyclophosphamide 750mg/m2 intravenous bolus over 10 minutes 9. Hydrocortisone 100mg intravenous when required for the relief of rituximab infusion related reactions 10. Salbutamol 2.5mg nebules when required for the relief of rituximab related bronchospasm Take Home Medicines 11. Etoposide 100mg/m2 once a day for 2 days oral (starting on day 2) 12. Prednisolone 100mg once a day on the morning of the next treatment** 13. Prednisolone 100mg once a day for 4 days oral (starting on day 2)** 14. Metoclopramide 10mg three times a day when required oral 15. Ondansetron 8mg twice a day for 3 days oral starting on the evening of day one of treatment Cycle 6 1. Warning – Check patient has taken the prednisolone dose* 2. Chlorphenamine 10mg intravenous 3. Paracetamol 1000mg oral 4. Rituximab 375mg/m2 intravenous infusion in 500ml sodium chloride 0.9% as per the rituximab administration guidelines 5. Ondansetron 8mg oral or intravenous injection 6. Vincristine 1.4mg/m2 (max 2mg) intravenous bolus in 50ml sodium chloride 0.9% over 10 minutes 7. Etoposide 150mg/m2 intravenous infusion in 1000ml sodium chloride 0.9% over 60 minutes Version 1.2 (Jan 2015) Page 9 of 11 Lymphoma- RCEOP-Cyclophosphamide-Etoposide-Prednisolone-Rituximab-Vincristine 8. Cyclophosphamide 750mg/m2 intravenous bolus over 10 minutes 9. Hydrocortisone 100mg intravenous when required for the relief of rituximab infusion related reactions 10. Salbutamol 2.5mg nebules when required for the relief of rituximab related bronchospasm Take Home Medicines 11. Etoposide 100mg/m2 once a day for 2 days oral (starting on day 2) 12. Prednisolone 100mg once a day for 4 days oral (starting on day 2) 13. Metoclopramide 10mg three times a day when required oral 14. Ondansetron 8mg twice a day for 3 days oral starting on the evening of day one of treatment Administration information * Please check the patient has taken prednisolone 100mg oral on the morning of rituximab administration. On occasions where individuals attend for treatment and have forgotten to take the prednisolone dose please administer prednisolone 100mg oral 30 minutes prior to rituximab administration. **The prednisolone may be dispensed as a single supply in one container or as two containers depending on local preference Version 1.2 (Jan 2015) Page 10 of 11 Lymphoma- RCEOP-Cyclophosphamide-Etoposide-Prednisolone-Rituximab-Vincristine DOCUMENT CONTROL Version Date Amendment Written By Approved By Header changed Toxicities removed Hepatic & renal tables updated Metoclopramide dose changed to 10mg Donna Kimber 1.2 Jan 2015 Bolus removed from intravenous Pharmacy bolus throughout text Technician Mucositis recommendation changed Disclaimer added Document control reordered “In patients over 70 years of age consider using vincristine 1mg. Where 1.1 July 2012 appropriate dose reduction of other agents may be considered at cycle one” changed to “Consider initial dose Rebecca Wills Pharmacist reduction in patients over 70 years of age.” 1 April 2012 None Rebecca Wills Pharmacist Dr Debbie Wright Pharmacist Rebecca Wills Pharmacist Dr Debbie Wright Pharmacist Dr Andrew Davies Consultant Medical Oncologist Dr Alison Milne 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 Hospitals 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 which occur as a result of following these guidelines. Version 1.2 (Jan 2015) Page 11 of 11 Lymphoma- RCEOP-Cyclophosphamide-Etoposide-Prednisolone-Rituximab-Vincristine
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MyelomaRCDCyclophosphamideDexamethasoneLenalidomidel(RCD)Ver1

Description: Chemotherapy Protocol MULTIPLE MYELOMA RCD-CYCLOPHOSPHAMIDE-DEXAMETHASONE-LENALIDOMIDE There are multiple versions of this protocol in use. Please ensure you have the correct protocol for the relevant diagnosis. Regimen Multiple Myeloma – RCD-Cyclophosphamide-Dexamethasone-Lenalidomide Indication Relapsed or refractory myeloma in patients having received at least one prior therapy Toxicity Drug Adverse Effect Cyclophosphamide Dysuria, haemorrrhagic cystitis (rare), taste disturbances Dexamethasone Lenalidomide Weight gain, GI disturbances, hyperglycaemia, CNS disturbances, cushingoid changes, glucose intolerance Peripheral neuropathy, pneumonia, infections, venous thrombotic events, respiratory dysfunction, rashes, hypokalaemia, hypomagnesaemia, hypocalcaemia, teratogenic risk, GI disturbances, flu-like symptoms. The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Monitoring FBC, LFTs and U&Es prior to each cycle Paraprotein and or light chains prior to each cycle Calcium and magnesium levels at regular intervals throughout treatment Perform a venous thromboembolism (VTE) risk assessment prior to starting treatment. Prescribe thromboprophylaxis for patients with additional risk factors Monitor thyroid function at the start of treatment and every six months thereafter. Regular monitoring of blood glucose is considered good practice Version 1 (May 2016) Page 1 of 11 Multiple Myeloma-RCD-Cyclophosphamide-Dexamethasone-Lenalidomide 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 symptomatic of anaemia or has a haemoglobin of less than 8g/dL. Dose modifications based on haematological parameters apply to cyclophosphamide only. Please note it is likely that myelosuppression prior to initial treatment in previously untreated patients will be a reflection of bone marrow infiltration. Unless there is evidence suggesting another cause, patients should be given at least the first cycle of treatment with unmodified doses. Dose modifications for haematological toxicity apply to lenalidomide only. Version 1 (May 2016) Page 2 of 11 Multiple Myeloma-RCD-Cyclophosphamide-Dexamethasone-Lenalidomide Consider growth factor support as an alternative to the options below, particularly where there is evidence of bone marrow suppression. Neutrophils (x109/L) 1 or more Less than 1 Platelets (x109/L) 50 or more Less than 50 Dose Modifications (lenalidomide) 100% 1st Occurrence Delay until recovery has occurred. Restart at full dose. 2nd Occurrence Delay until recovery has occurred. Restart at a dose of 15mg. 3rd Occurrence Delay until recovery has occurred. Restart at a dose of 10mg. 3rd Occurrence Delay until recovery has occurred. Restart at a dose of 5mg. Dose Modifications (lenalidomide) 100% 1st Occurrence Delay until recovery has occurred. Restart at a dose of 15mg. 2nd Occurrence Delay until recovery has occurred. Restart at a dose of 10mg. 3rd Occurrence Delay until recovery has occurred. Restart at a dose of 5mg. Hepatic Impairment Drug Bilirubin μmol/L AST/ALT units/L Dose (% of original dose) Clinical decision. Cyclophosphamide more than 30 or Evidence that exposure to active 2-3xULN metabolites may not be increased, suggesting dose reduction may not be necessary. Lenalidomide No dose adjustments needed Version 1 (May 2016) Page 3 of 11 Multiple Myeloma-RCD-Cyclophosphamide-Dexamethasone-Lenalidomide Renal Impairment Drug Cyclophosphamide Creatinine Clearance (ml/min) more than 20 10-20 less than 10 or serum creatinine greater than 300micromol/L Dose (% of original dose) 100% 75% omit Lenalidomide Greater than 50 100% 30-50 Less than 30 Less than 30 and requiring dialysis Start treatment with 10mg once a day. The dose may be escalated to 15 mg once daily after 2 cycles if patient is not responding to treatment and is tolerating the treatment Start treatment with 15mg on alternate days 5 mg once a day On dialysis days, the dose should be administered following dialysis. 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. Lenalidomide Allergic reaction or hypersensitivity NCI-CTC grade 2 then withhold treatment until symptoms have resolved to grade 1 or below, restart treatment at a daily dose of 15mg once a day. For NCI-CTC grade 3 or above then discontinue lenalidomide. Desquamating rash of NCI-CTC grade 3 and above or grade 4 non-desquamating rash, discontinue lenalidomide. There is an increased risk of thrombosis and some form of prophylaxis is recommended. A low molecular weight heparin or warfarin should be prescribed initially. If patients are treated with either a low molecular weight heparin or warfarin consider switching patients to aspirin after six cycles of therapy or after maximum response is achieved. A high index of suspicion for venous thrombo-embolism should be maintained. If a venous thrombosis or embolism NCI-CTC grade 3 or above then stop treatment and start anticoagulation. Lenalidomide may be reinstated at the clinician’s discretion, if the patient is fully anti-coagulated. Due to the potential for teratogenicity all women of child bearing potential are required to ensure adequate contraception, including a barrier method, is used. Additionally a negative Version 1 (May 2016) Page 4 of 11 Multiple Myeloma-RCD-Cyclophosphamide-Dexamethasone-Lenalidomide pregnancy test is required prior to commencing each cycle of therapy. Men are required to undertake to use a barrier method of contraception. In general for all other non-haematological NCI-CTC grade 3 and above toxicities delay treatment until the adverse effect has resolved to NCI-CTC grade 1 or below. Reduce the daily dose to 15mg. On subsequent occurrences delay until recovery the dose may then be reduced to 10mg and 5mg consecutively. If a dose of 5mg is not tolerated treatment should be stopped. Dexamethasone For patients who are elderly or unable to tolerate the standard dose of dexamethasone the dose may be reduced to 20mg once a day in the morning. Regimen 28 day cycle until disease progression (26 cycles will be set in ARIA) Drug Dose Cyclophosphamide* 500mg Days 1, 8 Administration Oral Dexamethasone** 40mg once a day in the morning 1, 8, 15, 22 Oral Lenalidomide 25mg once a day in the morning 1-21 incl. Oral *Cyclophosphamide should generally be stopped after 12 months of treatment or earlier if a maximum response is achieved. **20mg dose is recommended in those with frailty and co-morbidities. Dexamethasone may be stopped when the maximal response is reached. Dose Information Cyclophosphamide is available as 50mg tablets Dexamethasone is available as 500microgram and 2mg tablets Lenalidomide is available as 25mg, 15mg, 10mg and 5mg tablets Administration Information Dexamethasone should be taken in the mornings, with or after food. Cyclophosphamide tablets should be swallowed whole with a full glass of water Lenalidomide capsules should be swallowed whole, not chewed Version 1 (May 2016) Page 5 of 11 Multiple Myeloma-RCD-Cyclophosphamide-Dexamethasone-Lenalidomide Additional Therapy Antiemetics - metoclopramide 10mg three times a day when required oral - ondansetron 8mg once a day on days 1, 8 oral Consider allopurinol 300mg once a day for 7 days in cycle 1 only Thromboprophylaxis a low molecular weight heparin according to local formulary choice. Aspirin may be considered after six cycles or when maximal response is achieved. Consider anti-infective prophylaxis in high risk patients, including: - aciclovir 400mg twice a day oral - co-trimoxazole 960mg once a day oral on Monday, Wednesday and Friday only oral 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 Patient, prescriber and supplying pharmacy must comply with a pregnancy prevention programme. Every prescription must be accompanied with a completed Prescription Authorisation Form, which must be sent back to Celgene. 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. Coding Procurement – X71.5 Delivery – X73.1 References 1.Kumar S, Lacy M, Hayman S et al. Lenalidomide, cyclophosphamide and dexamethasone (CRd) for newly diagnosed multiple myeloma: results from a phase 2 trial. Am J Haematol 2011; 86(8): 640-5 2.Schey S, Morgan G, Ramasamy K et al. The addition of cyclophosphamide to lenalidomide and dexamethasone in multiply relapsed/refractory myeloma patients; a phase I/II study. Br J Haem 2010; 150 ;3 ;326-333 Version 1 (May 2016) Page 6 of 11 Multiple Myeloma-RCD-Cyclophosphamide-Dexamethasone-Lenalidomide REGIMEN SUMMARY RCD-Cyclophosphamide-Dexamethasone-Lenalidomide Cycle 1 Take Home Medicines 1. Warning – Pregnancy Prevention Programme Administration Instructions Lenalidomide is associated with a pregnancy prevention programme. Please ensure this is completed for all patients. 2. Cyclophosphamide 500mg once a day on days 1 and 8 oral Administration Instructions Please supply two doses of cyclophosphamide; ONE dose to be taken on day 1 and ONE dose to be taken on day 8 of the cycle. This may be dispensed as a single supply in one container or as separate supplies according to local practice. Oral chemotherapy. Only available as 50mg tablets, please ensure dose modifications occur in multiples of 50mg. Swallow whole, not chewed with plenty of water. 3. Dexamethasone 40mg once a day on days 1, 8, 15 and 22 oral Administration Instructions Please supply four doses of dexamethasone; ONE dose to be taken on days 1, 8, 15 and 22 of the cycle. This may be dispensed as a single supply in one container or as separate supplies according to local practice. Take in the morning with or after food. 4. Lenalidomide 25mg once a day for 21 days oral Administration Instructions Lenalidomide is associated with a pregnancy prevention programme. Please ensure this is completed for all patients. Oral chemotherapy. Available as 25mg, 15mg, 10mg, 5mg and 2.5mg capsules, please ensure dose modifications occur in multiples of these strengths. Swallow whole, not chewed with plenty of water. 5. Metoclopramide 10mg three times a day when required oral Administration Instructions When required for the relief of nausea. Please supply 28 tablets or nearest original pack size 6. Ondansetron 8mg once a day on day 1 and 8 oral Administration Instructions Please supply two doses of ondansetron; ONE dose to be taken on day 1 and ONE dose to be taken on day 8 of the cycle. This may be dispensed as a single supply in one container or as separate supplies according to local practice. Take 15-30 minutes prior to cyclophosphamide therapy 7. Allopurinol 300mg once a day for 7 days only oral Administration Instructions Take with or after food with plenty of water. Please supply 7 days. 8. Aciclovir 400mg twice a day for 28 days oral Administration Instructions Please supply 28 days or an original pack if appropriate 9. Co-trimoxazole 960mg once a day on Monday, Wednesday and Friday only for 28 days oral Administration Instructions Co-trimoxazole 960mg once a day on Mondays, Wednesdays and Fridays. Please supply 28 days. This may be dispensed as 480mg twice a day on Mondays, Wednesdays and Fridays according to local practice. 10. 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 Version 1 (May 2016) Page 7 of 11 Multiple Myeloma-RCD-Cyclophosphamide-Dexamethasone-Lenalidomide - 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 28 days or nearest original pack size. 11. Thromboprophylaxis according to local formulary choice; Administration Instructions The choice of thromboprophylaxis is dependent on local formularly choice and may include; - dalteparin 5000units once a day subcutaneous injection - enoxaparin 40mg once a day subcutaneous injection - heparin 5000units twice a day subcutaneous injection Please supply 28 days or nearest original pack size. Cycle 2-12 inclusive Take Home Medicines 12. Warning – Pregnancy Prevention Programme Administration Instructions Lenalidomide is associated with a pregnancy prevention programme. Please ensure this is completed for all patients. Oral chemotherapy. 13. Cyclophosphamide 500mg once a day on days 1 and 8 oral Administration Instructions Please supply two doses of cyclophosphamide; ONE dose to be taken on day 1 and ONE dose to be taken on day 8 of the cycle. This may be dispensed as a single supply in one container or as separate supplies according to local practice. Oral chemotherapy. Only available as 50mg tablets, please ensure dose modifications occur in multiples of 50mg. Swallow whole, not chewed with plenty of water. 14. Dexamethasone 40mg once a day on days 1, 8, 15, 22 oral Administration Instructions Please supply four doses of dexamethasone; ONE dose to be taken on days 1, 8, 15 and 22 of the cycle. This may be dispensed as a single supply in one container or as separate supplies according to local practice. Take in the morning with or after food. 15. Lenalidomide 25mg once a day for 21 days oral Administration Instructions Lenalidomide is associated with a pregnancy prevention programme. Please ensure this is completed for all patients. Oral chemotherapy. Available as 25mg, 15mg, 10mg, 5mg and 2.5mg capsules, please ensure dose modifications occur in multiples of these strengths. Swallow whole, not chewed with plenty of water. 16. Metoclopramide 10mg three times a day when required for nausea oral Administration Instructions When required for the relief of nausea. Please supply 28 tablets or nearest original pack size 17. Ondansetron 8mg once a day on day 1 and 8 oral Administration Instructions Please supply two doses of ondansetron; ONE dose to be taken on day 1 and ONE dose to be taken on day 8 of the cycle. This may be dispensed as a single supply in one container or as separate supplies according to local practice. 18. Aciclovir 400mg twice a day for 28 days oral Administration Instructions Please supply 28 days or an original pack if appropriate Version 1 (May 2016) Page 8 of 11 Multiple Myeloma-RCD-Cyclophosphamide-Dexamethasone-Lenalidomide 19. Co-trimoxazole 960mg once a day on Monday, Wednesday and Friday only for 28 days oral Administration Instructions Co-trimoxazole 960mg once a day on Mondays, Wednesdays and Fridays. Please supply 28 days. This may be dispensed as 480mg twice a day on Mondays, Wednesdays and Fridays according to local practice. 20. 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 28 days or nearest original pack size. 21. Thromboprophylaxis according to local formulary choice; Administration Instructions The choice of thromboprophylaxis is dependent on local formularly choice and may include; - dalteparin 5000units once a day subcutaneous injection - enoxaparin 40mg once a day subcutaneous injection - heparin 5000units twice a day subcutaneous injection Please supply 28 days or nearest original pack size. Cycle 13 onwards Take Home Medicines 22. Warning – Pregnancy Prevention Programme Administration Instructions Lenalidomide is associated with a pregnancy prevention programme. Please ensure this is completed for all patients. Dexamethasone 40mg once a day on days 1, 8, 15, 22 oral Administration Instructions Please supply four doses of dexamethasone; ONE dose to be taken on days 1, 8, 15 and 22 of the cycle. This may be dispensed as a single supply in one container or as separate supplies according to local practice. Take in the morning with or after food. 23. Lenalidomide 25mg once a day for 21 days oral Administration Instructions Lenalidomide is associated with a pregnancy prevention programme. Please ensure this is completed for all patients. Oral chemotherapy. Available as 25mg, 15mg, 10mg, 5mg and 2.5mg capsules, please ensure dose modifications occur in multiples of these strengths. Swallow whole, not chewed with plenty of water. 24. Metoclopramide 10mg three times a day when required for nausea oral Administration Instructions When required for the relief of nausea. Please supply 28 tablets or nearest original pack size 25. Ondansetron 8mg once a day on day 1 and 8 oral Please supply two doses of ondansetron; ONE dose to be taken on day 1 and ONE dose to be taken on day 8 of the cycle. This may be dispensed as a single supply in one container or as separate supplies according to local practice. Version 1 (May 2016) Page 9 of 11 Multiple Myeloma-RCD-Cyclophosphamide-Dexamethasone-Lenalidomide 26. Aciclovir 400mg twice a day for 28 days oral Administration Instructions Please supply 28 days or an original pack if appropriate 27. Co-trimoxazole 960mg once a day on Monday, Wednesday and Friday only for 28 days oral Administration Instructions Co-trimoxazole 960mg once a day on Mondays, Wednesdays and Fridays. Please supply 28 days. This may be dispensed as 480mg twice a day on Mondays, Wednesdays and Fridays according to local practice. 28. 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 28 days or nearest original pack size. 29. Thromboprophylaxis according to local formulary choice; Administration Instructions The choice of thromboprophylaxis is dependent on local formularly choice and may include; - dalteparin 5000units once a day subcutaneous injection - enoxaparin 40mg once a day subcutaneous injection - heparin 5000units twice a day subcutaneous injection Please supply 28 days or nearest original pack size. Version 1 (May 2016) Page 10 of 11 Multiple Myeloma-RCD-Cyclophosphamide-Dexamethasone-Lenalidomide DOCUMENT CONTROL Version Date Amendment Written By Approved By 1 May 2016 None Rebecca Wills 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 (May 2016) Page 11 of 11 Multiple Myeloma-RCD-Cyclophosphamide-Dexamethasone-Lenalidomide
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Clarithromycin-Dexamethasone_40_Pomalidomide

Description: Chemotherapy Protocol Myeloma Clarithromycin-Dexamethasone (40)-Pomalidomide Regimen • Myeloma – Clarithromycin-Dexamethasone (40)-Pomalidomide Indication • Pomalidomide, in combination with dexamethasone, is recommended as an option for treating multiple myeloma in adults at third or subsequent relapse; that is, after 3 previous treatments including both lenalidomide and bortezomib. • This protocol with a dose of dexamethasone of 40mg is recommended for those aged 75 years or below. Toxicity Drug Clarithromycin Dexamethasone Pomalidomide Adverse Effect Rash, hyperhidrosis, gastrointestinal disturbances, insomnia, headaches Weight gain, gastrointestinal disturbances, hyperglycaemia, CNS disturbances, cushingoid changes, glucose intolerance. Teratogenicity, cardiac failure, atrial fibrillation, thromboembolic events, interstitial lung disease, pneumonia, neutropenia, thrombocytopenia, leucopenia, anaemia, decreased appetite, dyspnoea, cough, gastrointestinal disturbance, bone pain, muscle spasm, fatigue, pyrexia, peripheral oedema, renal failure, peripheral neuropathy, skin reactions. The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Monitoring Drugs • FBC at baseline, then every two weeks for the first 8 weeks of treatment (the full cycle may be dispensed on day 1). Thereafter monitor prior to each cycle. • U&Es, Ca2+ and LFTs prior to day one of each cycle of treatment. • Paraprotein and/or light chains prior to each cycle. • For all women of childbearing potential a negative pregnancy test must be obtained within the 3 days prior to starting pomalidomide. The test must be repeated every 4 weeks (every 2 weeks in women with irregular menstrual cycles) with the final test 4 weeks after the last dose of pomalidomide. Version 1 (May 2018) Page 1 of 10 Myeloma – Clarithromycin-Dexamethasone (40)-Pomalidomide • All patients should be tested for hepatitis B virus (HBV) before initiating treatment with pomalidomide. Those patients who test positive for HBV infection should be discussed with a consultation specialist in HBV prior to initiating treatment with pomalidomide. Pomalidomide in combination with dexamethasone should be used cautiously in patients previously infected with HBV, including patients who are antiHBc positive but HBsAg negative. These patients should be closely monitored for signs and symptoms of active HBV infection throughout therapy. • Perform a venous thromboembolism (VTE) risk assessment prior to starting treatment. Prescribe thromboprophylaxis. • Regular monitoring of blood glucose is considered good practice. 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 the use of erythropoietin according to NICE TA323 if patient symptomatic of anaemia or where the haemoglobin is less than 8g/dL (80g/L). Consider growth factor support as an alternative to the options below, particularly where there is evidence of bone marrow suppression. To initiate a new cycle of pomalidomide, the neutrophil count must be 1x109/L or greater and the platelet count must be 50x109/L or greater. No dose reductions are necessary for either clarithromycin or dexamethasone for haematological toxicity. Version 1 (May 2018) Page 2 of 10 Myeloma – Clarithromycin-Dexamethasone (40)-Pomalidomide Neutrophils (x109/L) Less than 0.5x109/L or febrile neutropenia (fever greater than or equal to 38.5°C and neutrophils less than1) Dose Modifications Interrupt pomalidomide treatment and monitor FBC weekly. Once neutrophils recover to 1x109/L, resume pomalidomide at a dose of 3mg once a day. For each subsequent drop to less than 0.5x109/L Platelets (x109/L) Less than 25x109/L Interrupt pomalidomide treatment and monitor FBC weekly, once neutrophils recover to 1x109/L or greater then resume pomalidomide at 1mg less than previous dose. Dose Modifications Interrupt pomalidomide treatment and monitor FBC weekly. Once platelets recover to 50x109/L or greater resume pomalidomide at a dose of 3mg once a day. For each subsequent drop to Interrupt pomalidomide and monitor FBC weekly and once less than 25x109/L platelets recover to 50x109/L, resume pomalidomide at 1mg less than previous dose. Hepatic Impairment Patients with serum total bilirubin greater than 2mg/dL were excluded from clinical studies. Hepatic impairment has a modest effect on the pharmacokinetics of pomalidomide. No adjustment of the starting dose of pomalidomide is required for patients with hepatic impairment as defined by the Child-Pugh criteria. However, patients with hepatic impairment should be carefully monitored for adverse reactions and dose reduction or interruption of pomalidomide should be used as needed. However, as markedly elevated levels of alanine aminotransferase and bilirubin have been observed in patients treated with pomalidomide together with cases of hepatitis that resulted in treatment discontinuation, regular monitoring of liver function is recommended for the first 6 months of treatment with pomalidomide and as clinically indicated thereafter. Renal Impairment No dose adjustment of pomalidomide is required for patients with renal impairment. Where patients are receiving haemodialysis, the pomalidomide dose should be taken following haemodialysis. Pomalidomide Cardiac Failure Cardiac failure is a known common adverse reaction associated with pomalidomide treatment (ie occurs in between 1/10 and 1/100 patients who take pomalidomide). In most cases, this side effect occurs in patients with cardiac disease or cardiac risk factors and within six months of starting pomalidomide. Pomalidomide can cause atrial fibrillation, which may precipitate cardiac failure. Monitor for signs and symptoms of cardiac impairment. Interstitial Lung Disease Intersitial lung disease (ILD), including cases of pneumonitis, have been observed with pomalidomide. Careful assessment of patients with an acute onset or unexplained worsening of pulmonary symptoms should be performed to exclude ILD. Pomalidomide Version 1 (May 2018) Page 3 of 10 Myeloma – Clarithromycin-Dexamethasone (40)-Pomalidomide should be interrupted during investigation of these symptoms and if ILD is confirmed, appropriate treatment should be initiated. Pomalidomide should only be resumed after a thorough evaluation of the benefits and the risks. Pregnancy As pomalidomide is structurally related to thalidomide a teratogenic effect is expected, therefore, it must not be taken during pregnancy. All women of child bearing potential (even if they have amenorrhoea) must use one effective method of pregnancy prevention at least 4 weeks before therapy, during therapy and even in the case of dose interruptions, and for at least a further 4 weeks after stopping therapy. Additionally a negative pregnancy test is required prior to commencing each cycle of therapy. Men are required to undertake to use a barrier method of contraception. The conditions of the Celgene Pregnancy Prevention Programme must be fulfilled for all patients unless there is reliable evidence that the patient does not have childbearing potential. Skin Pomalidomide interruption or discontinuation should be considered for WHO grade 2-3 skin rash. Pomalidomide must be discontinued for angioedema, WHO grade 4 rash, exfoliative or bullous rash, or if Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN) or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is suspected, and should not be resumed following discontinuation from these reactions. Venous Thromboembolism (VTE) Patients receiving pomalidomide in combination with dexamethasone have developed venous thromboembolic events (predominantly deep vein thrombosis and pulmonary embolism) and arterial thrombotic events (myocardial infarction and cerebrovascular accident). Appropriate VTE prophylaxis is recommended. All patients should receive aspirin unless contra-indicated. Patients deemed to be at high risk of VTE should receive a low molecular weight heparin. The duration of thromboprophylaxis remains unclear but guided by risk factors such as active disease (e.g. for the first 4 to 6 months of treatment until disease control achieved) and de-escalated or discontinued unless there are ongoing significant risk factors. If patients are treated with a low molecular weight heparin consider switching patients to aspirin after six cycles of therapy or after maximum response is achieved. A high index of suspicion for venous thromboembolism should always be maintained. If a venous thrombosis or embolism NCI-CTC grade 3 or above occurs then stop treatment and start full anticoagulation. Pomalidomide may be restarted at the clinician’s discretion, once the patient is fully anti-coagulated. Modifiable risk factors for thromboembolic events should be managed wherever possible to reduce the risk of VTE (e.g. smoking cessation; control of hypertension and hyperlipidaemia). Medicines that may increase the risk of thromboembolism, such as oestrogens and erythropoietic agents, should be used with caution during pomalidomide treatment. For all other NCI-CTCAE grade 3 or 4 adverse reactions, judged to be related to pomalidomide, stop treatment. Restart treatment when the adverse reaction has resolved to Version 1 (May 2018) Page 4 of 10 Myeloma – Clarithromycin-Dexamethasone (40)-Pomalidomide NCI-CTC grade 2 or below at 1 mg less than the previous dose, or at the consultants discretion. Dexamethasone Dose Level 3 (starting) 2 1 Dose 40mg 20mg 10mg If recovery from toxicities is prolonged beyond 14 days, then the dose of dexamethasone will be decreased by one dose level. Toxicity Grade (NCI-CTC) Dose modification Dyspepsia 1-2 3 or above Oedema 3 or above Confusion or mood alteration 2 or above Muscle weakness 2 or above Hyperglycaemia 3 or above Acute pancreatitis Other 3 or above Maintain dose and treat with histamine (H2) antagonist or proton pump inhibitor. Decrease by one dose level if symptoms persist. Interrupt dose until symptoms are controlled. Add H2 blocker or proton pump inhibitor and decrease one dose level when dose restarted. Use diuretics as needed and decrease dose by one dose level. Interrupt dose until symptoms resolve. When dose restarted decrease dose by one dose level. Interrupt dose until the muscle weakness is grade 1 or below. Restart with dose decreased by one level. Decrease dose by one dose level. Treat with insulin or oral hypoglycaemic agents as needed Discontinue patient from dexamethasone treatment regimen. Stop dexamethasone dosing until adverse event resolves to grade 2 or below. Resume with dose reduced by one level. Regimen 28 day cycle until disease progression or intolerance (12 cycles will be set in Aria) Version 1 (May 2018) Page 5 of 10 Myeloma – Clarithromycin-Dexamethasone (40)-Pomalidomide Drug Clarithromycin Dexamethasone Pomalidomide Dose 500mg twice a day 40mg 4mg once a day Days 1-28 inclusive 1, 8 15 and 22 1-21 inclusive Administration Oral Oral Oral Dose Information • Pomalidomide is available as 1mg, 2mg, 3mg and 4mg hard capsules. • Clarithromycin is available as 250mg and 500mg tablets • Dexamethasone is available as 500microgram, 2mg and 4mg tablets Administration Information • Pomalidomide should be taken at the same time each day. The capsules should be swallowed whole, preferably with water, with or without food and not be opened, broken or chewed. • Pomalidomide can cause drowsiness it may be advisable to take it at night. • If a dose of pomalidomide is forgotten on one day, the normal prescribed dose should be taken the next day. Patients should not adjust the dose to make up for missing a dose on previous days. • It is recommended to press only on one end of the pomalidomide capsule to remove it from the blister thereby reducing the risk of capsule deformation or breakage. • Dexamethasone should be taken in the morning with or immediately after food. • All prescriptions for pomalidomide must be accompanied by an electronic prescription authorisation form (ePAF). Additional therapy • Thromboprophylaxis, the choice depending on risk factors and duration of therapy. • Consider allopurinol 300mg once a day for seven days for the first cycle only oral • Consider anti-infective prophylaxis including; - aciclovir 400mg twice a day oral - co-trimoxazole 960mg once a day oral on Monday, Wednesday and Friday only - fluconazole 50mg once a day oral • Bisphosphonates in accordance with local policies. • Mouthwashes according to local or national policy on the treatment of mucositis. • 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 Version 1 (May 2018) Page 6 of 10 Myeloma – Clarithromycin-Dexamethasone (40)-Pomalidomide Additional Information • The National Patient Safety Alert on oral chemotherapy (NPSA/2008/RRR001) must be followed in relation to pomalidomide. • It must be made clear to all staff, including those in the community, that pomalidomide should only be prescribed under the supervision of a consultant haematologist. • Patients should be assessed for suitability for oral chemotherapy prior to starting treatment. • For all patients taking pomalidomide; the patient, prescriber and supplying pharmacy must comply with the Celgene pregnancy prevention programme (PPP). • Clarithromycin and pomalidomide interact with many other drugs. Always check for drug interactions and take appropriate actions where necessary. Coding • Procurement – X71.5 • Delivery – X73.1 References 1. Celgene Limited (2016). Imnovid 4mg Summary of Product Characteristics. Electronic Medicines Compendium. Online at http://www.medicines.org.uk/emc/medicine/29475, accessed 25 January 2017. 2. National Institute for Health and Care Excellence (2017). Pomalidomide for multiple myeloma previously treated with lenalidomide and bortezomib. [TA427]. London: National Institute for Health and Care Excellence. 3. Celgene Limited (2013). Imnovid (Pomalidomide) Healthcare Professionals Information Pack UK Version 1.0. 4. Dimopoulos MA, Palumbo A, Corrodini P et al. Safety and efficacy of pomalidomide plus low-dose dexamethasone in STRATUS (MM-010): a phase 3b study in refractory multiple myeloma. Blood (2016); 128 (4): 497-503. Version 1 (May 2018) Page 7 of 10 Myeloma – Clarithromycin-Dexamethasone (40)-Pomalidomide REGIMEN SUMMARY Clarithromycin-Dexamethasone (40)-Pomalidomide Cycle 1 Take home medicines 1. Clarithromycin 500mg twice a day for 28 days oral 2. Dexamethasone 40mg on days 1, 8, 15 and 22, oral Administration Information 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. Warning – Pregnancy Prevention Programme Administration Instructions Pomalidomide is associated with a pregnancy prevention programme. Please ensure this is completed for all patients. 4. Pomalidomide 4mg once a day on days 1-21 oral Administration Information Oral chemotherapy Pregnancy prevention programme Take at the same time each day. Swallow the capsules whole, preferably with water, with or without food. 5. Allopurinol 300mg once a day for 7 days, oral Administration information Take in the morning with food and plenty of water. This should be supplied for the first cycle. 6. Aciclovir 400mg twice a day for 28 days oral Administration Instructions Please supply 28 days or an original pack if appropriate. 7. Co-trimoxazole 960mg once a day on Monday, Wednesday and Friday only for 28 days oral Administration Instructions Co-trimoxazole 960mg once a day on Mondays, Wednesdays and Fridays. Please supply 28 days. This may be dispensed as 480mg twice a day on Mondays, Wednesdays and Fridays according to local practice. 8. Fluconazole 50mg once a day for 28 days oral 9. 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 supply 28 days or the nearest original pack size. 10. Thromboprophylaxis according to risk factors Administration Instructions The choice of thromboprophylaxis is dependent on risk factors. Aspirin 75mg once a day in the morning may be prescribed for low risk individuals. For those deemed high risk consider a low molecular weight heparin such as; - dalteparin 5000units once a day subcutaneous injection - enoxaparin 40mg once a day subcutaneous injection Version 1 (May 2018) Page 8 of 10 Myeloma – Clarithromycin-Dexamethasone (40)-Pomalidomide - heparin 5000units twice a day subcutaneous injection Please supply 28 days or nearest original pack size. Cycle 2 onwards Take home medicines 1. Clarithromycin 500mg twice a day for 28 days oral 2. Dexamethasone 40mg on days 1, 8, 15 and 22, oral Administration Information 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. Warning – Pregnancy Prevention Programme Administration Instructions Pomalidomide is associated with a pregnancy prevention programme. Please ensure this is completed for all patients. 4. Pomalidomide 4mg once a day on days 1-21 oral Administration Information Oral chemotherapy Pregnancy prevention programme Take at the same time each day. Swallow the capsules whole, preferably with water, with or without food. 5. Aciclovir 400mg twice a day for 28 days oral Administration Instructions Please supply 28 days or an original pack if appropriate. 6. Co-trimoxazole 960mg once a day on Monday, Wednesday and Friday only for 28 days oral Administration Instructions Co-trimoxazole 960mg once a day on Mondays, Wednesdays and Fridays. Please supply 28 days. This may be dispensed as 480mg twice a day on Mondays, Wednesdays and Fridays according to local practice. 7. Fluconazole 50mg once a day for 28 days oral 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 supply 28 days or the nearest original pack size. 9. Thromboprophylaxis according to risk factors Administration Instructions The choice of thromboprophylaxis is dependent on risk factors. Aspirin 75mg once a day in the morning may be prescribed for low risk individuals. For those deemed high risk consider a low molecular weight heparin such as; - dalteparin 5000units once a day subcutaneous injection - enoxaparin 40mg once a day subcutaneous injection - heparin 5000units twice a day subcutaneous injection Please supply 28 days or nearest original pack size. Version 1 (May 2018) Page 9 of 10 Myeloma – Clarithromycin-Dexamethasone (40)-Pomalidomide DOCUMENT CONTROL Version Date Amendment Written By Approved By 1 May 2018 None Mrs Eleanor Taylor Pharmacist Dr Deborah Wright Pharmacist Dr N Ryman 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 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 (May 2018) Page 10 of 10 Myeloma – Clarithromycin-Dexamethasone (40)-Pomalidomide
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Clarithromycin-Dexamethasone_20_Pomalidomide

Description: Chemotherapy Protocol Myeloma Clarithromycin-Dexamethasone (20)-Pomalidomide Regimen • Myeloma – Clarithromycin-Dexamethasone (20)-Pomalidomide Indication • Pomalidomide, in combination with low‑dose dexamethasone, is recommended as an option for treating multiple myeloma in adults at third or subsequent relapse; that is, after 3 previous treatments including both lenalidomide and bortezomib. • This protocol with a dose of dexamethasone of 20mg is recommended for those aged over 75 years. Toxicity Drug Clarithromycin Dexamethasone Pomalidomide Adverse Effect Rash, hyperhidrosis, gastrointestinal disturbances, insomnia, headaches Weight gain, gastrointestinal disturbances, hyperglycaemia, CNS disturbances, cushingoid changes, glucose intolerance. Teratogenicity, cardiac failure, atrial fibrillation, thromboembolic events, interstitial lung disease, pneumonia, neutropenia, thrombocytopenia, leucopenia, anaemia, decreased appetite, dyspnoea, cough, gastrointestinal disturbance, bone pain, muscle spasm, fatigue, pyrexia, peripheral oedema, renal failure, peripheral neuropathy, skin reactions. The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Monitoring Drugs • FBC at baseline, then every two weeks for the first 8 weeks of treatment (the full cycle may be dispensed on day 1). Thereafter monitor prior to each cycle. • U&Es, Ca2+ and LFTs prior to day one of each cycle of treatment. • Paraprotein and/or light chains prior to each cycle. • For all women of childbearing potential a negative pregnancy test must be obtained within the 3 days prior to starting pomalidomide. The test must be repeated every 4 weeks (every 2 weeks in women with irregular menstrual cycles) with the final test 4 weeks after the last dose of pomalidomide. Version 1 (May 2018) Page 1 of 11 Myeloma – Clarithromycin-Dexamethasone (20)-Pomalidomide • All patients should be tested for hepatitis B virus (HBV) before initiating treatment with pomalidomide. Those patients who test positive for HBV infection should be discussed with a consultation specialist in HBV prior to initiating treatment with pomalidomide. Pomalidomide in combination with dexamethasone should be used cautiously in patients previously infected with HBV, including patients who are antiHBc positive but HBsAg negative. These patients should be closely monitored for signs and symptoms of active HBV infection throughout therapy. • Perform a venous thromboembolism (VTE) risk assessment prior to starting treatment. Prescribe thromboprophylaxis. • Regular monitoring of blood glucose is considered good practice. 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 the use of erythropoietin according to NICE TA323 if patient symptomatic of anaemia or where the haemoglobin is less than 8g/dL (80g/L). Consider growth factor support as an alternative to the options below, particularly where there is evidence of bone marrow suppression. To initiate a new cycle of pomalidomide, the neutrophil count must be 1x109/L or greater and the platelet count must be 50x109/L or greater. No dose reductions are necessary for either clarithromycin or dexamethasone for haematological toxicity. Version 1 (May 2018) Page 2 of 11 Myeloma – Clarithromycin-Dexamethasone (20)-Pomalidomide Neutrophils (x109/L) Less than 0.5x109/L or febrile neutropenia (fever greater than or equal to 38.5°C and neutrophils less than1) Dose Modifications Interrupt pomalidomide treatment and monitor FBC weekly. Once neutrophils recover to 1x109/L, resume pomalidomide at a dose of 3mg once a day. For each subsequent drop to less than 0.5x109/L Platelets (x109/L) Less than 25x109/L Interrupt pomalidomide treatment and monitor FBC weekly, once neutrophils recover to 1x109/L or greater then resume pomalidomide at 1mg less than previous dose. Dose Modifications Interrupt pomalidomide treatment and monitor FBC weekly. Once platelets recover to 50x109/L or greater resume pomalidomide at a dose of 3mg once a day. For each subsequent drop to Interrupt pomalidomide and monitor FBC weekly and once less than 25x109/L platelets recover to 50x109/L, resume pomalidomide at 1mg less than previous dose. Hepatic Impairment Patients with serum total bilirubin greater than 2mg/dL were excluded from clinical studies. Hepatic impairment has a modest effect on the pharmacokinetics of pomalidomide. No adjustment of the starting dose of pomalidomide is required for patients with hepatic impairment as defined by the Child-Pugh criteria. However, patients with hepatic impairment should be carefully monitored for adverse reactions and dose reduction or interruption of pomalidomide should be used as needed. However, as markedly elevated levels of alanine aminotransferase and bilirubin have been observed in patients treated with pomalidomide together with cases of hepatitis that resulted in treatment discontinuation, regular monitoring of liver function is recommended for the first 6 months of treatment with pomalidomide and as clinically indicated thereafter. Renal Impairment No dose adjustment of pomalidomide is required for patients with renal impairment. Where patients are receiving haemodialysis, the pomalidomide dose should be taken following haemodialysis. Pomalidomide Cardiac Failure Cardiac failure is a known common adverse reaction associated with pomalidomide treatment (ie occurs in between 1/10 and 1/100 patients who take pomalidomide). In most cases, this side effect occurs in patients with cardiac disease or cardiac risk factors and within six months of starting pomalidomide. Pomalidomide can cause atrial fibrillation, which may precipitate cardiac failure. Monitor for signs and symptoms of cardiac impairment. Interstitial Lung Disease Intersitial lung disease (ILD), including cases of pneumonitis, have been observed with pomalidomide. Careful assessment of patients with an acute onset or unexplained worsening of pulmonary symptoms should be performed to exclude ILD. Pomalidomide Version 1 (May 2018) Page 3 of 11 Myeloma – Clarithromycin-Dexamethasone (20)-Pomalidomide should be interrupted during investigation of these symptoms and if ILD is confirmed, appropriate treatment should be initiated. Pomalidomide should only be resumed after a thorough evaluation of the benefits and the risks. Pregnancy As pomalidomide is structurally related to thalidomide a teratogenic effect is expected, therefore, it must not be taken during pregnancy. All women of child bearing potential (even if they have amenorrhoea) must use one effective method of pregnancy prevention at least 4 weeks before therapy, during therapy and even in the case of dose interruptions, and for at least a further 4 weeks after stopping therapy. Additionally a negative pregnancy test is required prior to commencing each cycle of therapy. Men are required to undertake to use a barrier method of contraception. The conditions of the Celgene Pregnancy Prevention Programme must be fulfilled for all patients unless there is reliable evidence that the patient does not have childbearing potential. Skin Pomalidomide interruption or discontinuation should be considered for WHO grade 2-3 skin rash. Pomalidomide must be discontinued for angioedema, WHO grade 4 rash, exfoliative or bullous rash, or if Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN) or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is suspected, and should not be resumed following discontinuation from these reactions. Venous Thromboembolism (VTE) Patients receiving pomalidomide in combination with dexamethasone have developed venous thromboembolic events (predominantly deep vein thrombosis and pulmonary embolism) and arterial thrombotic events (myocardial infarction and cerebrovascular accident). Appropriate VTE prophylaxis is recommended. All patients should receive aspirin unless contra-indicated. Patients deemed to be at high risk of VTE should receive a low molecular weight heparin. The duration of thromboprophylaxis remains unclear but guided by risk factors such as active disease (e.g. for the first 4 to 6 months of treatment until disease control achieved) and de-escalated or discontinued unless there are ongoing significant risk factors. If patients are treated with a low molecular weight heparin consider switching patients to aspirin after six cycles of therapy or after maximum response is achieved. A high index of suspicion for venous thromboembolism should always be maintained. If a venous thrombosis or embolism NCI-CTC grade 3 or above occurs then stop treatment and start full anticoagulation. Pomalidomide may be restarted at the clinician’s discretion, once the patient is fully anti-coagulated. Modifiable risk factors for thromboembolic events should be managed wherever possible to reduce the risk of VTE (e.g. smoking cessation; control of hypertension and hyperlipidaemia). Medicines that may increase the risk of thromboembolism, such as oestrogens and erythropoietic agents, should be used with caution during pomalidomide treatment. For all other NCI-CTCAE grade 3 or 4 adverse reactions, judged to be related to pomalidomide, stop treatment. Restart treatment when the adverse reaction has resolved to NCI-CTC grade 2 or below at 1 mg less than the previous dose, or at the consultants discretion. Version 1 (May 2018) Page 4 of 11 Myeloma – Clarithromycin-Dexamethasone (20)-Pomalidomide Dexamethasone Dose Level 3 (starting) 2 1 Dose 20mg 12mg 8mg If recovery from toxicities is prolonged beyond 14 days, then the dose of dexamethasone will be decreased by one dose level. Toxicity Grade (NCI-CTC) Dose modification Dyspepsia 1-2 3 or above Oedema 3 or above Confusion or mood alteration 2 or above Muscle weakness 2 or above Hyperglycaemia 3 or above Acute pancreatitis Other 3 or above Maintain dose and treat with histamine (H2) antagonist or proton pump inhibitor. Decrease by one dose level if symptoms persist. Interrupt dose until symptoms are controlled. Add H2 blocker or proton pump inhibitor and decrease one dose level when dose restarted. Use diuretics as needed and decrease dose by one dose level. Interrupt dose until symptoms resolve. When dose restarted decrease dose by one dose level. Interrupt dose until the muscle weakness is grade 1 or below. Restart with dose decreased by one level. Decrease dose by one dose level. Treat with insulin or oral hypoglycaemic agents as needed Discontinue patient from dexamethasone treatment regimen. Stop dexamethasone dosing until adverse event resolves to grade 2 or below. Resume with dose reduced by one level. Regimen 28 day cycle until disease progression or intolerance (12 cycles will be set in Aria) Drug Dose Days Administration Version 1 (May 2018) Page 5 of 11 Myeloma – Clarithromycin-Dexamethasone (20)-Pomalidomide Clarithromycin 500mg twice a day 1-28 inclusive Oral Dexamethasone 20mg 1, 8 15 and 22 Oral Pomalidomide 4mg once a day 1-21 inclusive Oral Dose Information • Pomalidomide is available as 1mg, 2mg, 3mg and 4mg hard capsules. • Clarithromycin is available as 250mg and 500mg tablets • Dexamethasone is available as 500microgram, 2mg and 4mg tablets Administration Information • Pomalidomide should be taken at the same time each day. The capsules should be swallowed whole, preferably with water, with or without food and not be opened, broken or chewed. • Pomalidomide can cause drowsiness it may be advisable to take it at night. • If a dose of pomalidomide is forgotten on one day, the normal prescribed dose should be taken the next day. Patients should not adjust the dose to make up for missing a dose on previous days. • It is recommended to press only on one end of the pomalidomide capsule to remove it from the blister thereby reducing the risk of capsule deformation or breakage. • Dexamethasone should be taken in the morning with or immediately after food. • All prescriptions for pomalidomide must be accompanied by an electronic prescription authorisation form (ePAF). Additional therapy • Thromboprophylaxis, the choice depending on risk factors and duration of therapy. • Consider allopurinol 300mg once a day for seven days for the first cycle only oral • Consider anti-infective prophylaxis including (included in ARIA); - aciclovir 400mg twice a day oral - co-trimoxazole 960mg once a day oral on Monday, Wednesday and Friday only - fluconazole 50mg once a day oral • Bisphosphonates in accordance with local policies. • Mouthwashes according to local or national policy on the treatment of mucositis. Version 1 (May 2018) Page 6 of 11 Myeloma – Clarithromycin-Dexamethasone (20)-Pomalidomide • 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 Alert on oral chemotherapy (NPSA/2008/RRR001) must be followed in relation to pomalidomide. • It must be made clear to all staff, including those in the community, that pomalidomide should only be prescribed under the supervision of a consultant haematologist. • Patients should be assessed for suitability for oral chemotherapy prior to starting treatment. • For all patients taking pomalidomide; the patient, prescriber and supplying pharmacy must comply with the Celgene pregnancy prevention programme (PPP). • Clarithromycin and pomalidomide interact with many other medications. Always check for drug interactions. Coding • Procurement – X71.5 • Delivery – X73.1 References 1. Celgene Limited (2016). Imnovid 4mg Summary of Product Characteristics. Electronic Medicines Compendium. Online at http://www.medicines.org.uk/emc/medicine/29475, accessed 25 January 2017. 2. National Institute for Health and Care Excellence (2017). Pomalidomide for multiple myeloma previously treated with lenalidomide and bortezomib. [TA427]. London: National Institute for Health and Care Excellence. 3. Celgene Limited (2013). Imnovid (Pomalidomide) Healthcare Professionals Information Pack UK Version 1.0. 4. Dimopoulos MA, Palumbo A, Corrodini P et al. Safety and efficacy of pomalidomide plus low-dose dexamethasone in STRATUS (MM-010): a phase 3b study in refractory multiple myeloma. Blood (2016); 128 (4): 497-503. Version 1 (May 2018) Page 7 of 11 Myeloma – Clarithromycin-Dexamethasone (20)-Pomalidomide REGIMEN SUMMARY Clarithromycin-Dexamethasone (20)-Pomalidomide Cycle 1 Take home medicines 1. Clarithromycin 500mg twice a day for 28 days oral 2. Dexamethasone 20mg on days 1, 8, 15 and 22, oral Administration Information 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. Warning – Pregnancy Prevention Programme Administration Instructions Pomalidomide is associated with a pregnancy prevention programme. Please ensure this is completed for all patients. 4. Pomalidomide 4mg once a day on days 1-21 oral Administration Information Oral chemotherapy Pregnancy prevention programme Take at the same time each day. Swallow the capsules whole, preferably with water, with or without food. 5. Allopurinol 300mg once a day for 7 days, oral Administration information Take in the morning with food and plenty of water. This should be supplied for the first cycle. 6. Aciclovir 400mg twice a day for 28 days oral Administration Instructions Please supply 28 days or an original pack if appropriate. 7. Co-trimoxazole 960mg once a day on Monday, Wednesday and Friday only for 28 days oral Administration Instructions Co-trimoxazole 960mg once a day on Mondays, Wednesdays and Fridays. Please supply 28 days. This may be dispensed as 480mg twice a day on Mondays, Wednesdays and Fridays according to local practice. 8. Fluconazole 50mg once a day for 28 days oral 9. 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 supply 28 days or the nearest original pack size. Version 1 (May 2018) Page 8 of 11 Myeloma – Clarithromycin-Dexamethasone (20)-Pomalidomide 10. Thromboprophylaxis according to risk factors Administration Instructions The choice of thromboprophylaxis is dependent on risk factors. Aspirin 75mg once a day in the morning may be prescribed for low risk individuals. For those deemed high risk consider a low molecular weight heparin such as; - dalteparin 5000units once a day subcutaneous injection - enoxaparin 40mg once a day subcutaneous injection - heparin 5000units twice a day subcutaneous injection Please supply 28 days or nearest original pack size. Cycle 2 onwards Take home medicines 1. Clarithromycin 500mg twice a day for 28 days oral 2. Dexamethasone 20mg on days 1, 8, 15 and 22, oral Administration Information 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. Warning – Pregnancy Prevention Programme Administration Instructions Pomalidomide is associated with a pregnancy prevention programme. Please ensure this is completed for all patients. 4. Pomalidomide 4mg once a day on days 1-21 oral Administration Information Oral chemotherapy Pregnancy prevention programme Take at the same time each day. Swallow the capsules whole, preferably with water, with or without food. 5. Aciclovir 400mg twice a day for 28 days oral Administration Instructions Please supply 28 days or an original pack if appropriate. 6. Co-trimoxazole 960mg once a day on Monday, Wednesday and Friday only for 28 days oral Administration Instructions Co-trimoxazole 960mg once a day on Mondays, Wednesdays and Fridays. Please supply 28 days. This may be dispensed as 480mg twice a day on Mondays, Wednesdays and Fridays according to local practice. 7. Fluconazole 50mg once a day for 28 days oral 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 supply 28 days or the nearest original pack size. Version 1 (May 2018) Page 9 of 11 Myeloma – Clarithromycin-Dexamethasone (20)-Pomalidomide 9. Thromboprophylaxis according to risk factors Administration Instructions The choice of thromboprophylaxis is dependent on risk factors. Aspirin 75mg once a day in the morning may be prescribed for low risk individuals. For those deemed high risk consider a low molecular weight heparin such as; - dalteparin 5000units once a day subcutaneous injection - enoxaparin 40mg once a day subcutaneous injection - heparin 5000units twice a day subcutaneous injection Please supply 28 days or nearest original pack size. Version 1 (May 2018) 11 Page 10 of Myeloma – Clarithromycin-Dexamethasone (20)-Pomalidomide DOCUMENT CONTROL Version Date Amendment Written By Approved By 1 May 2018 None Mrs Eleanor Taylor Pharmacist Dr Deborah Wright Pharmacist Dr N Ryman 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 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 (May 2018) 11 Page 11 of Myeloma – Clarithromycin-Dexamethasone (20)-Pomalidomide
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Ipilimumab-Nivolumab

Description: Chemotherapy Protocol SKIN CANCER IPILIMUMAB (3mg/kg)-NIVOLUMAB (1mg/kg) Regimen • Skin – Ipilimumab (3mg/kg)-Nivolumab (1mg/kg) Indication • Ipilimumab in combination with nivolumab is recommended for the treatment of advanced, unresectable metastatic melanoma. • WHO performance status 0, 1 Toxicity Drug Ipilimumab Nivolumab Adverse Effect Colitis, diarrhoea, dermatitis, neuropathy, hypothyroidism, hepatotoxicity, infusion related reactions, hypophysitis Fatigue, rash, pruritis, pneumonitis, diarrhoea, nausea, electrolyte disturbances, hepatitis and other immune-related adverse reactions. The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full details. Monitoring Regimen • FBC, LFTs and U&Es prior to day one of each cycle • Blood pressure prior to treatment • Thyroid function tests prior to staring treatment and then before each administration (cycle) or when clinically indicated. Dose Modifications The dose modifications listed are for haematological, liver and renal function and some drug specific toxicities. Ipilimumab and nivolumab belong to the immunotherapy class of cancer treatments. Autoimmune toxicities are most frequently noted and can be life threatening. If autoimmune toxicities occur delaying treatment should be considered while investigations or treatments are organised. Some, but not all, toxicities mandate cessation of treatment. Please seek guidance from relevant site specific specialist teams or oncologists / haematologists with experience of prescribing these agents. Clinicians should be aware that the current funding approval for ipilimumab and Version 1.3 (July 2019) Page 1 of 9 Skin-Ipilimumab(3mg/kg)-Nivolumab(1mg/kg) nivolumab precludes further treatment after an interruption of 12 weeks or longer; this situation may change. Refer to the latest version of the European Society of Medical Oncology guidelines; Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up(1). Haematological Consider blood transfusion or erythropoietin if patient symptomatic of anaemia or has a haemoglobin of less than 8g/dL There is little need to adjust the dose of ipilimumab or nivolumab for haematological toxicity. Instead dose delay criteria apply for all drug-related adverse events (regardless of whether or not the event is attributed to nivolumab, ipilimumab, or both). Both drugs must be delayed until treatment can resume. Hepatic Impairment For patients with pre-existing mild hepatic impairment no dose adjustment is recommended for either ipilimumab or nivolumab. Immune related hepatic reactions are associated with ipimumab and nivolumab. For a hepatitis associated with an AST / ALT of 3-5xULN and / or a total bilirubin of 1.5-3xULN then withhold treatment and administer corticosteroids. Upon improvement to NCI-CTC grade 1 hepatic injury begin to taper the corticosteroid over a period of one month. The combination may be re-started when the liver function remains at NCI-CTC grade 1 following corticosteroid taper. Both ipilimumab and nivolumab should be permanently discontinued when the hepatic injury does not improve to at least NCI-CTC grade 1 within 12 weeks of the last dose, the corticosteroid dose cannot be reduced to 10mg or less of prednisolone or equivalent per day within 12 weeks or any NCI-CTC grade 3 or above reaction. The combination should be permanently discontinued in the first instance when hepatitis develops that is associated with an AST / ALT equal to or greater than 5xULN or where the bilirubin is greater than 3xULN. Renal Impairment No dose adjustment is required in patients with pre-existing mild or moderate renal impairment. Data from patients with severe renal impairment are too limited to draw conclusions on this population. Severe nephritis or renal dysfunction has been observed with ipilimumab and nivolumab treatment. Patients should be monitored for signs and symptoms of nephritis and renal dysfunction. Most patients present with asymptomatic increases in serum creatinine. Disease-related aetiologies should be ruled out. For NCI-CTC grade 2 or 3 serum creatinine elevation, both agents should be withheld and corticosteroids initiated. Upon improvement to NCI-CTC grade 1 initiate corticosteroid taper over at least one month. Treatment may be resumed when the Version 1.3 (July 2019) Page 2 of 9 Skin-Ipilimumab(3mg/kg)-Nivolumab(1mg/kg) reaction remains at NCI-CTC grade 1 or below following tapering of the corticosteroid. The combination should be permanently discontinued when the serum creatinine does not improve to at least NCI-CTC grade 1 within 12 weeks of the last dose, the corticosteroid dose cannot be reduced to 10mg or less of prednisolone or equivalent per day within 12 weeks or in the case of a recurrent NCI-CTC grade 3 reaction. For NCI-CTC Grade 4 serum creatinine elevation, the ipilimumab and nivolumab must be permanently discontinued, and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents. 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. Ipilimumab and nivolumab is associated with inflammatory adverse reactions resulting from increased or excessive immune activity, likely to be related to its pharmacology. Immune-related adverse reactions, which can be severe or life-threatening, may involve the gastrointestinal, liver, skin, nervous, endocrine, or other organ systems. Most occur during treatment, however, onset months after the last dose has been reported. Unless an alternate aetiology has been identified, diarrhoea, increased stool frequency, bloody stool, LFT elevations, rash and endocrinopathy must be considered inflammatory and ipilimumab-related. Early diagnosis and appropriate management are essential to minimise life threatening complications. Endocrine Ipilimumab and nivolumab can cause inflammation of the endocrine system organs, specifically hypophysitis, hypopituitarism, adrenal insufficiency, and hypothyroidism. This may present with nonspecific symptoms resembling other causes such as brain metastasis or underlying disease. If there are any signs of adrenal crisis such as severe dehydration, hypotension, or shock, immediate administration of intravenous corticosteroids with mineralocorticoid activity is recommended, the patient must be evaluated for presence of sepsis or infections. If there are signs of adrenal insufficiency but the patient is not in crisis, further investigations should be considered including laboratory and imaging assessment. Evaluation of laboratory results to assess endocrine function may be performed before corticosteroid therapy is initiated. If pituitary imaging or laboratory tests of endocrine function are abnormal, a short course of high-dose corticosteroid therapy is recommended to treat the gland inflammation. The scheduled dose of ipilimumab and nivolumab should be omitted. It is currently unknown if the corticosteroid treatment reverses the gland dysfunction. Appropriate hormone replacement should also be initiated. Long-term hormone replacement therapy may be necessary. Once symptoms or laboratory abnormalities are controlled and overall patient improvement is evident, treatment with ipilimumab and nivolumab may be resumed and initiation of corticosteroid taper should be based on clinical judgment. Version 1.3 (July 2019) Page 3 of 9 Skin-Ipilimumab(3mg/kg)-Nivolumab(1mg/kg) Hypophysitis can present as a diffuse, heterogenous enlargement of the pituitary on a brain MRI but can be completely normal. When hypophysitis with pituitary dysfunction is suspected, blood tests including thyroid stimulating hormone (TSH), free T4, adrenocorticotropic stimulating hormone, cortisol, leutinizing hormone, and follicle-stimulating hormone should be obtained in women, and the first four plus testosterone in men. Typically the anterior pituitary axis is involved, affecting thyroid, gonadal, and adrenal function, but isolated axis dysfunction can be seen. Hypophysitis will cause low free T4 as well as TSH. Hypophysitis with clinically significant adrenal insufficiency and hypotension, dehydration, and electrolyte abnormalities such as hyponatremia and hyperkalemia constitutes adrenal crisis. Hospitalization and intravenous steroids with mineralocorticoid activity, such as methylprednisolone, should be initiated while waiting for laboratory results. Infection and sepsis should be ruled out with appropriate cultures and imaging. Prednisolone 1 mg/kg by mouth should be administered if patients are clinically stable. Steroids can usually be tapered over 30 days to achieve physiologic replacement levels. Thyroid hormone and/or testosterone replacement therapy may not be permanent, as the need for those hormones may wane over months in some patients. Cortisone replacement may also not be permanent in a modest portion of patients. Gastrointestinal Gastro-intestinal immune reactions include diarrhoea, increased frequency of bowel movements, abdominal pain or haematochezia, with or without fever. Diarrhoea or colitis occurring after initiation of ipilimumab and nivolumab must be promptly evaluated to exclude infectious or other alternate causes. Immune-related colitis is often associated with evidence of mucosal inflammation, with or without ulcerations and lymphocytic and neutrophilic infiltration. NCI-CTC grade 1 or 2 diarrhoea or suspected mild to moderate colitis may continue on the combination. Symptomatic treatment and close monitoring are advised. If mild to moderate symptoms recur or persist for 5-7 days, the scheduled dose of the agents should be omitted and consideration given to prescribing prednisolone 1 mg/kg orally once a day. If resolution to NCI-CTC grades 0-1 or return to baseline occurs, the ipilimumab and nivolumab may be resumed at the next scheduled dose. Doses omitted due to an adverse reaction must not be replaced. Consider endoscopy to confirm or rule out colitis if there is persistent NCI-CTC grade 2 diarrhoea or NCI-CTC grade 1 - 2 diarrhoea with bleeding. Ipilimumab and nivolumab must be discontinued if NCI-CTC grade 3 or 4 diarrhoea, colitis, peritoneal signs of bowel perforation, ileus or fever occur. High-dose intravenous corticosteroid therapy should be initiated immediately unless bowel perforation is present. Once diarrhoea and other symptoms are controlled, the initiation of corticosteroid taper should be based on clinical judgment (tapering over 6-8 weeks). In clinical trials, rapid tapering (over periods of less than 1 month) resulted in recurrence of diarrhoea or colitis in some patients. Consider alternative immunosuppressive therapy (eg single dose of infliximab 5mg/kg) if symptoms do not respond to steroids in 5-7 days. Neurological Unexplained motor neuropathy, muscle weakness, or sensory neuropathy lasting more than 4 days must be evaluated and other causes excluded. Version 1.3 (July 2019) Page 4 of 9 Skin-Ipilimumab(3mg/kg)-Nivolumab(1mg/kg) For patients with NCI-CTC grade 2, neuropathy likely related to be related to ipilimumab or nivolumab omit the scheduled dose. If the neurologic symptoms resolve to baseline, the patient may resume treatment at the next scheduled dose. Ipilimumab and nivolumab must be permanently discontinued in patients with NCICTC grade 3 or 4, sensory neuropathy. Patients must be treated according to local guidelines for management of sensory neuropathy. Skin A diffuse, erythematous maculopapular rash that can be intensely pruritic was observed in 47% to 68% of patients, starting an average of 3 to 4 weeks after ipilimumab or nivolumab. NCI-CTC grade 1 or 2 skin reactions may remain on therapy with symptomatic treatment such as topical corticosteroids and antihistamines. For mild to moderate rash or pruritus that persists for 1 to 2 weeks and does not improve with topical corticosteroids consider oral corticosteroid therapy (e.g. prednisolone 1 mg/kg once a day). For patients with NCI-CTC grade 3 symptomatic skin reactions, the scheduled dose of ipilimumab and nivolumab should be omitted. If initial symptoms improve to NCICTC grade 1 or resolve then the therapy may be resumed at the next scheduled dose. Ipilimumab and nivolumab must be permanently discontinued in patients with a NCI-CTC grade 4 rash or grade 3 pruritus and consideration given to systemic corticosteroid therapy. Other Immune-Related Adverse Reactions The following additional adverse reactions, suspected to be immune-related, have been reported and include uveitis, eosinophilia, lipase elevation, and glomerulonephritis. In addition, iritis, haemolytic anaemia, amylase elevations, multi-organ failure, and pneumonitis have been reported. If these occur at NCI-CTC grade 3 or above then consider immediate high-dose corticosteroid therapy and discontinuation of ipilimumab and nivolumab. For ipilimumab and / or nivolumab-related uveitis, iritis, or episcleritis, topical corticosteroid eyedrops should be considered as medically indicated. Regimen 21 day cycle for 4 cycles Drug Ipilimumab Nivolumab Dose 3mg/kg 1mg/kg Days 1 1 Route Intravenous infusion in 100ml sodium chloride 0.9% over 90 minutes Intravenous infusion in 50ml sodium chloride 0.9% over 30 minutes Version 1.3 (July 2019) Page 5 of 9 Skin-Ipilimumab(3mg/kg)-Nivolumab(1mg/kg) Followed by; 14 day cycle starting 3 weeks after the last dose of the combination of nivolumab and ipilimumab and continued for as long as clinical benefit is observed or until no longer tolerated Drug Dose Days Route Nivolumab 240mg 1 Intravenous infusion in 100ml sodium chloride 0.9% over 30 minutes OR 28 day cycle starting 6 weeks after the last dose of the combination of nivolumab and ipilimumab and continued for as long as clinical benefit is observed or until no longer tolerated Drug Dose Days Route Nivolumab 480mg 1 Intravenous infusion in 100ml sodium chloride 0.9% over 60 minutes Please note that due to the different cycle lengths the combination treatment will be set up as one regimen. This can then be discontinued and single agent nivolumab started. Dose Information • Ipilimumab will be dose banded according to the agreed bands • Nivolumab will be dose banded according to the agreed bands Administration Information Extravasation • Ipilimumab – neutral • Nivolumab - neutral Other • The nivolumab must be administered first during the combination phase of treatment. 30 minutes should elapse between both agents. • Ipilimumab should be administered using a low protein binding filter • The final concentration of ipilimumab should be between 1-4mg/ml • Nivolumab should be administered via a 0.2-1.2 micron a low protein binding filter. The polyethylene lined giving sets used for paclitaxel with a 0.22 micron filter are appropriate. Version 1.3 (July 2019) Page 6 of 9 Skin-Ipilimumab(3mg/kg)-Nivolumab(1mg/kg) Additional Therapy • No antiemetics are required • When required for infusion related reactions - chlorphenamine 10mg intravenous when required for the treatment of infusion related reactions - hydrocortisone sodium succinate 100mg intravenous when required for the treatment of infusion related reactions - paracetamol 1000mg oral when required for the relief of infusion related reactions • Gastric protection with a H2 antagonist may be considered in patients considered at high risk of GI ulceration or bleed. There is evidence that proton pump inhibitors may reduce the efficacy of the combination of ipilimumab and nivolumab Additional Information • The use of systemic corticosteroids, before starting treatment with ipilimumab should be avoided ipilimumab because of their potential interference with the pharmacodynamic activity and efficacy of ipilimumab. However, systemic corticosteroids can be used after starting ipilimumab to treat immune-related adverse reactions. The use of systemic corticosteroids after starting treatment does not appear to impair the efficacy of ipilimumab. Coding • Procurement – X70.8 • Delivery – X72.9 References 1. Haanen J, Carbonnel F, Robert C, Kerr K.M , Peters S, Larkin J, Jordan J on behalf of the ESMO Guidelines Committee. Management of toxicities from immunotherapy. ESMO clinical practice guidelines for diagnosis, treatment and follow up. Ann Oncol 2017; 28 (suppl 4): 119-142. 2. National Institute for Health and Clinical Excellence. Nivolumab in combination with ipilimumab for treating advanced melanoma. Technology Appraisal Guidance TA 400 (July 2016). Version 1.3 (July 2019) Page 7 of 9 Skin-Ipilimumab(3mg/kg)-Nivolumab(1mg/kg) REGIMEN SUMMARY Ipilimumab (3mg/kg)-Nivolumab (1mg/kg) Cycle 1, 2, 3 1. Nivolumab 1mg/kg intravenous infusion in 50ml sodium chloride 0.9% over 30 minutes Administration Instructions Ensure the patient has been given a nivolumab patient alert card. Administer before the ipilimumab infusion. Please leave 30 minutes between the administration of both agents 2. Ipilimumab 3mg/kg intravenous infusion in 100ml sodium chloride 0.9% over 90 minutes 3. Chlorphenamine 10mg intravenous when required for the treatment of infusion related reactions 4. Hydrocortisone sodium succinate 100mg intravenous when required for the treatment of infusion related reactions 5. Paracetamol 1000mg oral when required for the relief of infusion related reactions Administration Instructions Please check if the patient has taken paracetamol. Maximum dose is 4g per 24 hours. There should be 4 hours between doses Cycle 4 6. Warning – Consider single agent nivolumab Administration Instructions Consider prescribing single agent nivolumab 7. Nivolumab 1mg/kg intravenous infusion in 50ml sodium chloride 0.9% over 30 minutes Administration Instructions Ensure the patient has been given a nivolumab patient alert card. Administer before the ipilimumab infusion. Please leave 30 minutes between the administration of both agents 8. Ipilimumab 3mg/kg intravenous infusion in 100ml sodium chloride 0.9% over 90 minutes 9. Chlorphenamine 10mg intravenous when required for the treatment of infusion related reactions 10. Hydrocortisone sodium succinate 100mg intravenous when required for the treatment of infusion related reactions 11. Paracetamol 1000mg oral when required for the relief of infusion related reactions Administration Instructions Please check if the patient has taken paracetamol. Maximum dose is 4g per 24 hours. There should be 4 hours between doses Version 1.3 (July 2019) Page 8 of 9 Skin-Ipilimumab(3mg/kg)-Nivolumab(1mg/kg) DOCUMENT CONTROL Version Date Amendment Written By Approved By Infusion time for nivolumab 1.3 1mg/kg changed to 30min and July 2019 details of follow on monotherapy updated accordance with current Rebecca Wills Pharmacist SmPC Title change to include doses of 1.2 agents. July 2019 PPI recommendation changed Dose reduction removed from Dr Deborah Wright Pharmacist dose modification section 1.1 Feb 2018 Nivolumab 1mg/kg infusion volume changed to 50ml Dr Deborah Wright Pharmacist 1 Sept 2016 None Dr Deborah Wright Pharmacist Dr Deborah Wright Pharmacist Dr M Wheater Consultant Medical Oncologist Stuart Martin Pharmacist Dr M Wheater Consultant Medical Oncologist 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 1.3 (July 2019) Page 9 of 9 Skin-Ipilimumab(3mg/kg)-Nivolumab(1mg/kg)
Url: /Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/Skincancer/Ipilimumab-Nivolumab.pdf

HSCTAlemtuzumabFludarabineMelphalan-VUD-Methotrexate-GvHD

Description: Chemotherapy Protocol HAEMATOLOGY – HSCT ALLOGRAFT ALEMTUZUMAB-FLUDARABINE-MELPHALAN-METHOTREXATE (GVHD) Volunteer Unrelated Donor (VUD) Conditioning This regimen will only be available
Url: /Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/Transplant/HSCTAlemtuzumabFludarabineMelphalan-VUD-Methotrexate-GvHD.pdf

HSCTAlemtuzumabFludarabineMelphalan-Related_Methotrexate_GvHD

Description: Chemotherapy Protocol HAEMATOLOGY – HSCT ALLOGRAFT ALEMTUZUMAB-FLUDARABINE-MELPHALAN-METHOTREXATE (GvHD) RELATED DONOR CONDITIONING This regimen will only be available to prescribe
Url: /Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/Transplant/HSCTAlemtuzumabFludarabineMelphalan-Related-Methotrexate-GvHD.pdf

HSCTAlemtuzumabBusulphan-08-Fludarabine-VUD-Methotrexate-GvHD

Description: Chemotherapy Protocol HAEMATOLOGY – HSCT ALLOGRAFT ALEMTUZUMAB-BUSULFAN (8 doses)-FLUDARABINE-METHOTREXATE (GvHD) Volunteer Unrelated Donor (VUD) CONDITIONING This regimen will only
Url: /Media/UHS-website-2019/Docs/Chemotherapy-SOPs1/Transplant/HSCTAlemtuzumabBusulphan-8-Fludarabine-VUD-Methotrexate-GvHD.pdf

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