Fludarabine-Cyclophosphamide plus Rituximab (FC-R) for Chronic Lymphocytic Leukaemia

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1 DRUG ADMINISTRATION SCHEDULE First Cycle Only: Day Drug Dose Route Diluent Rate 1 Paracetamol 1gram Oral 1 Hydrocortisone 100mg IV bolus 1 Chlorphenamine 10mg IV bolus 1 Rituximab 375mg/m 2 IV infusion *250ml 0.9% Sodium Chloride See below Day Drug Dose Route Frequency Notes 1-5 Allopurinol 300mg ORAL Once Daily 5 days 2-6 Fludarabine 24mg/m 2 ORAL 2-6 Cyclophosphamide 150mg/m 2 ORAL breakfast time lunch time 2-6 Metoclopramide 10 mg ORAL three times daily 1 Co-trimoxazole 960mg ORAL Monday, Wednesday & Friday Until 6 months after fludarabine *Some centres may supply rituximab in 500ml on the first cycle to make the infusion rates easier to work with. Cycle 2 to 6: Day Drug Dose Route Diluent Rate 1 Paracetamol 1gram Oral 1 Hydrocortisone 100mg IV bolus 1 Chlorphenamine 10mg IV bolus 1 Rituximab 500mg/m 2 IV infusion 250ml 0.9% Sodium Chloride See below Day Drug Dose Route Frequency Notes 2-6 Fludarabine 24mg/m 2 ORAL breakfast time 2-6 Cyclophosphamide 150mg/m 2 ORAL lunch time 2-6 Metoclopramide 10 mg ORAL three times daily 1 Co-trimoxazole 960mg ORAL Monday, Wednesday & Friday Caution: There are other intravenous and oral schedules of Fludarabine & Cyclophosphamide with different doses. Select Protocol with Care! Until 6 months after fludarabine Page 1 of 5

2 Fludarabine Tablets are supplied in 10mg tablets, and Cyclophosphamide are supplied in 50mg tablets - suggested dose bands: Body Surface Area Cyclophosphamide Dose (at 150mg/m 2 ) Fludarabine Dose (at 24mg/m 2 ) m 2 250mg 40mg m 2 300mg 50mg CYCLE LENGTH AND NUMBER OF DAYS 28 Day cycle, usually given for up to 6 cycles APPROVED INDICATIONS First Line Treatment of B-Chronic Lymphocytic Leukaemia (B-CLL). Relapsed/Refractory Treatment of B-CLL ELIGIABILITY CRITERIA Binet Stage B or C EXCLUSION CRITERIA Inadequate renal function (CrCl < 30ml/min) Pregnancy / Breast Feeding Decompensated haemolytic anaemia. RECOMMENDED TAKE HOME MEDICATION All patients must have PCP Prophylaxis with Co-Trimoxazole 960mg three times per week (Mon, Wed, Fri) continuing for 6 months post chemotherapy. Allopurinol 300mg once daily on days 1 to 5 of the first cycle. Metoclopramide 10mg three times daily when required. INVESTIGATIONS / MONITORING REQUIRED Prior to first cycle: FBC, U&E s, LFT s, LDH, bone profile, DCT, bone marrow Prior to each cycle: FBC, U&E s, LFT s, bone profile ASSESSMENT OF RESPONSE Haematological response Palpable disease B symptoms REVIEW BY CLINICIAN Prior to each cycle (unless being seen by a nurse / pharmacist see below) NURSE / PHARMACIST LED REVIEW Nurse or pharmacist led review, within a locally agreed protocol, is acceptable on day 1 for all cycles except the first, and middle cycle. Page 2 of 5

3 ADMINISTRATION NOTES Patients requiring blood transfusion will require irradiated blood products. Patients receiving rituximab must be screened for Hepatitis B prior to starting treatment. Risk of hypersensitivity and anaphylaxis particularly during the first cycle for the first two hours of administration. Monitor patient every 15 minutes for first hour then every 30minutes. Symptoms usually resolve with interruption of rituximab and administration of antipyretic and antihistamines. Some patients will require oxygen, intravenous fluids (0.9% Sodium Chloride), bronchodilators (eg. nebulised salbutamol), and glucocorticoids (eg. IV hydrocortisone). Risk of severe hypersensitivity (cytokine release syndrome) increases when Peripheral Lymphocytes > 25 cells x10 9 /l treatment should only proceed with caution in this setting. Reducing the infusion rate or using a different therapy first line may be appropriate. Fludarabine tablets can be taken on an empty stomach or with food. Fludarabine tablets must be swallowed whole, with plenty of water. Ensure adequate contraception will be used if appropriate Ensure current CrCl has been assessed, and that any dose reduction necessary has been taken into account in prescribing May potentiate cardiotoxicitiy May cause tumour lysis syndrome in susceptible patients Will cause amenorrhea / testicular atrophy Rituximab Infusion Rates: First cycle of rituximab should commence at 50mg/hour and increase in rate by 50mg/hour every 30 minutes (to a maximum of 400mg/hour) provided the patient does not develop any signs of infusion reaction. Subsequent cycles (provided the previous cycle has been tolerated well) can start at 100mg/hour and increase by 100mg/hour every 30 minutes to a maximum of 400mg/hour. (Rapid infusion see below) The infusion rate can be calculated by: Blood Pressure, Pulse and Respiration rate should be measured every 15minutes for the first hour of infusion, and then every 30 minutes subsequently. Rapid Infusion: a few small studies have demonstrated that it is possible to give rituximab at a faster rate for the second or third cycle. This practice is unlicensed and clinicians wishing to follow this practice should check with their own trust prior to adopting this practice. The unlicensed nature of the infusion rate should be explained to patients at the time of consent. The rapid infusion rate used is 20% of the dose over 30 minutes (100ml/hour), followed by the remaining 80% over just 60minutes (200ml/hour). Rapid infusion should only be considered for patients who have shown no signs of adverse reaction during previous infusions, and is contra-indicated in patients Page 3 of 5

4 with high tumour bulk/burden or with high circulating lymphocyte counts. TOXICITIES Common: Myelosuppression, Fatigue, Immunosupression. Infusion reactions Less Common: Nausea, Vomiting, Flushing, Rash, Allergic rash, Haemolysis, Haemorrhagic cystitis, Peripheral neuropathy. DOSE MODIFICATION / TREATMENT DELAYS Haematological Toxicity: (Note: where haematological disease is affecting bone marrow function, lower treatment parameters may be acceptable. This should be clearly documented for the specific patient.) Delay treatment on Day 1 if ANC < 1.5 x 10 9 cells/l or PLT < 100 x 10 9 cells/l If treatment is delayed for more than 14 days: ANC PLT Dose % Renal Function: Fludarabine is extensively renally excreted and significant dose reduction is required for patients with mild renal failure: CrCl Fludarabine Dose Cyclophosphamide Dose >70ml/min 100% 100% 30 70ml/min 50% 100% 20-30ml/min 100% 10-20ml/min Contra-indicated 75% <10ml/min 50% TREATMENT LOCATION Suitable for self administration in patients own homes, under the supervision of haematology teams from Level 1 4 Haematology Services. REFERENCES: Summary of Product Characteristics, Bayer Schering Pharma, Feb Summary of Product Characteristics, Roche. April CLL4 Trial Protocol (Chronic Lymphocytic Leukaemia Trial 4: A Randomised Comparison of Chlorambucil, Fludarabine and Fludarabine Plus Cyclophosphamide.). Accessed at: Tadeusz Robak, Sergey I Moiseev, Anna Dmoszynska, et al. Rituximab, Fludarabine, and Cyclophosphamide (R-FC) Prolongs Progression Free Survival in Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) Compared with FC Alone: Final Results from the International Randomized Phase III REACH Trial. ASH 2008 Page 4 of 5

5 Document Control Document Title: R-FC NECN protocol CRP09 H039 Document No: Author: CRP09 H039 Calum Polwart, Network Pharmacist NECN Current Version: 1.3 Reviewed by: Calum Polwart Approved by: Diane Plews / Anne Lennard Date 19 June 2014 Due for Review: June 2016 Summary of Changes 1.0a Final version agreed 1.1a Relapsed / Refractory indication added Protocol reviewed. Renal impairment advice for Cyclophosphamide added. Document number amended. Formatting updated. Allopurinol for first cycle only added. Hepatitis testing in Rituximab added. Page 5 of 5