Regimen : Irinotecan+Modified de Gramont (FOLFIRI)

Transcription

1 Regimen : Irinotecan+Modified de Gramont (FOLFIRI) Indication Treatment of first line or second line palliative therapy for stage IV or relapsed colorectal cancer. Regimen details Administration For performance status 0 and 1 patients only. Day Drug Route 1 Irinotecan 180mg/m 2 IV infusion 1 Calcium Folinate (Folinic acid) 350 mg IV infusion 1 Fluorouracil 400mg/m 2 IV bolus 1-3* Fluorouracil 2400mg/m 2 over 46 hours *i.e. single dose, commenced day 1, finished day 3 IV infusion Order of administration: irinotecan and calcium folinate first (together or calcium folinate first, followed by irinotecan), fluorouracil bolus second, fluorouracil infusion third. Calcium folinate and irinotecan may be administered concomitantly via a 3-way tap/y-site connector. Irinotecan is administered in ml of Sodium Chloride 0.9% or Glucose 5%. The first dose of irinotecan must be administered over 90 minutes. If this is well-tolerated, subsequent doses may be administered over 30 minutes. Calcium folinate is administered by intravenous infusion in ml of Sodium Chloride 0.9% or Glucose 5% over 2 hours. The smaller fluorouracil dose is administered by slow intravenous bolus into the side-arm of a fast flowing drip of 0.9% sodium chloride. The larger fluorouracil dose is administered by intravenous infusion (via central venous catheter and ambulatory infusor device or continuous peripheral IV infusion) over 46 hours. (If given via peripheral infusion, the dose is split in two and given in 2x1 litre 0.9% Sodium Chloride). Calcium levofolinate is NOT equivalent to calcium folinate/folinic acid/calcium leucovorin. (Calcium levofolinate is a single isomer of folinic acid and the dose is generally 175mg i.e. half that of calcium folinate). Frequency Every 14 days Maximum 12 cycles Extravasation Irinotecan is an irritant (Group 3) Fluorouracil is an inflammatant (Group 2) Calcium Folinate (Folinic acid) is neutral (Group 1) Premedication Give atropine 300 micrograms (0.3 mg) subcutaneously prior to each treatment to reduce acute cholinergic syndrome. Emetogenicity This regimen has moderate emetogenic potential refer to local protocol Additional recommended supportive medication Other cholinergic symptoms may occur during or shortly after infusion of irinotecan, including rhinorrhoea, increased salivation, lacrimation, diaphoresis and flushing. These should be treated with atropine 0.3 mg 0.6 mg IV or SC. Blood pressure and heart rate should be monitored. Controlled document Document Number Version Number Page 1 of 6

2 Pre-treatment evaluations Regular investigations Prochlorperazine should be avoided on the same day as irinotecan treatment due to the increased incidence of akathisia. Give written information sheet concerning diarrhoea. Take Loperamide 4mg at the first loose stool and then 2mg every 2 hours until diarrhoea-free (for up to 48 hours). If it persists >24 hours start Ciprofloxacin 500 mg bd. Mouthwashes as per local policy. Pyridoxine 50 mg tds reduces the severity of plantar-palmar erythrodyesthesia (PPE). It should be given for any grade PPE and should be continued until the end of treatment. FBC Baseline results valid for 7 days U+E Baseline results valid for 7 days LFT Baseline results valid for 7 days CEA FBC U+E LFT CEA (perform monthly) CT scan Baseline results valid for 7 days Results valid for 72 hrs Results valid for 7 days Results valid for 7 days Results valid for 7 days Perform after 6 cycles of treatment Standard limits for Neutrophil count 1.0 x 10 9 /L administration to go Platelet count 100 x 10 9 /L ahead if blood results not within range, Creatinine clearance 30ml/min authorisation to administer AST/ALT 1.5 x ULN must be given by prescriber/consultant Bilirubin 26micromol/L modifications Haematological toxicity Renal impairment Hepatic impairment Defer therapy for 1 week if neutrophils <1.0 x 10 9 /L or platelets < 100 x 10 9 /L If there is > 1 week delay due to haematological toxicity, reduce fluorouracil and irinotecan doses by 20%. CrCl (ml/min) Irinotecan Fluorouracil % 100% 100% % 100% 100% <10 50% Consider dose reduction 100% Bilirubin (micromol/l) ALT/AST (x ULN) Irinotecan Fluorouracil Folinic Acid 26 < % 100% 100% % Consider reducing dose by 33% * Contraindicated Consider reducing dose by 50% * Folinic Acid 100% 100% >85 or >5 Contraindicated Contra-indicated *s may be increased back to 100% if there is no toxicity. Note: significant hepatic impairment may indicate disease progression: always discuss deteriorating hepatic function with consultant. Controlled document Document Number Version Number Page 2 of 6

3 Diarrhoea Grade Definition Irinotecan If > Grade 2 on Day 1, withhold treatment. If <Grade 2 within 2 weeks, treat with reduced doses. If diarrhoea > Grade 2 after 2 weeks, discontinue treatment. NCI Common toxicity criteria 1-2 Up to 6 stools/day or mild increase in loose watery colostomy output 3 Increase of 7-9 stools/day or incontinence, malabsorption; or severe increase in loose watery colostomy output 4 Increase of 10 or more stools/day or grossly bloody colostomy output or loose watery colostomy output requiring parenteral support; dehydration Fluorouracil 100% 100% 100% Folinic Acid 150mg/m 2 Bolus: 320mg/m 2 Infusion: 2000mg/m 2 100% 120mg/m 2 Bolus: 240mg/m 2 Infusion: 1600mg/m 2 100% Toxicity Definition adjustment Febrile neutropenia Stomatitis/Mucositis Diarrhoea (see above for dose reductions) ANC <0.5 x 10 9 /L plus fever requiring IV antibiotics +/- hospitalisation Grade 2 Grade 3 Reduce subsequent cycles of fluorouracil by 50% and reduce dose of irinotecan to 120mg/m 2. 20% 50%. Grade 4 Discontinue treatment or defer until Grade 1 and reduce all subsequent doses of fluorouracil by 50% - consultant decision. Diarrhoea may be life-threatening and requires prompt, aggressive treatment. Early diarrhoea or abdominal cramps occurring within the first 24 hours is treated with atropine mg IV or SC. DO NOT ADMINISTER LOPERAMIDE DURING THIS 24 HOUR PERIOD. Late diarrhoea (diarrhoea occurring >24 hours after treatment) has a median onset of 5 days post-treatment with this regimen and must be treated with Loperamide. The Loperamide dose is higher than recommended by the manufacturer. Instruct patient to have Loperamide on hand and start treatment at the first poorly formed or loose stool, or earliest onset of more frequent stool than usual. Take Loperamide 4mg at the first loose stool and then take 2mg every 2 hours until diarrhoea-free for 12 hours after last loose stool (4 mg every 4 hours may be taken over night). If diarrhoea persists >24 hours start Ciprofloxacin 500 mg bd and contact local Trust for Controlled document Document Number Version Number Page 3 of 6

4 Adverse effects the contents of the table indicate the adverse effects that should be documented on consent to treatment forms Significant drug interactions For full details consult product literature/reference texts Palmar-Plantar Erythrodyesthesia (PPE) further advice/supportive care. In no instance should Loperamide be administered for more than 48 consecutive hours at these doseswithout appropriate medical supervision due to the risk of paralytic ileus. Grade 2 Grade 3/4 Rare or serious side effects Palmar-plantar erythema (Hand-Foot Syndrome) Myelosuppression and neutropenic sepsis Cardiac toxicity including tachycardia, and coronary artery spasm Ocular toxicity including excessive lacrimation, blocked tear ducts, visual changes and photophobia. Interstitial pulmonary disease Teratogenicity/Infertility Other 20% 50% Frequently occurring side effects Mucositis/Stomatitis Diarrhoea Alopecia Nausea & vomiting Asthenia Acute cholinergic syndrome Thrombocytopenia Transient cerebellar syndrome, confusion, thrombophlebitis, hypokalaemia Warfarin/coumarin anticoagulants: increased or fluctuating anticoagulant effects. Avoid if possible: in the first instance, consider switching patient to a low molecular weight heparin during treatment or if the patient continues taking an oral anticoagulant monitor the INR at least once a week and adjust dose accordingly. Irinotecan: CYP3A4 substrates: concomitant administration of irinotecan with strong CYP3A4 inhibitors (e.g. ketoconazole) or inducers (e.g. rifampicin, carbamazepine, phenytoin, St. John s Wort) may alter the metabolism of irinotecan. Aprepitant: increases irinotecan plasma levels Prochlorperazine: increased risk of akathisia Citalopram: increased risk of myopathy and rhabdomyolysis Tobacco: decreases irinotecan plasma levels Fluorouracil: Allopurinol: may potentiate cytotoxic effect-avoid concomitant use Clozapine: increased risk of agranulocytosis, avoid concomitant use Digoxin tablets: fluorouracil may reduce digoxin absorption (give digoxin in liquid form) Metronidazole and Cimetidine: inhibit metabolism of fluorouracil (increased exposure and risk of toxicity) Phenytoin: reduced absorption of phenytoin. Calcium Folinate: Antiepileptic drugs (phenobarbital, primidone, phenytoin): may increase the frequency of seizures Anti-folates (co-trimoxazole/trimethoprim, pyrimethamine): efficacy may be reduced by concomitant use of leucovorin. Controlled document Document Number Version Number Page 4 of 6

5 Comments Use with caution in patients with Gilbert s Syndrome (due to the increased risk of irinotecan-induced toxicity). Dihydropyrimidine dehydrogenase (DPD) deficiency can result in severe toxicity secondary to reduced fluorouracil metabolism avoid use in patients with known DPD deficiency Cardiotoxicity has been associated with fluoropyrimidine therapy, with adverse events being more common in patients with a prior history of coronary artery disease. Caution must be taken in patients with a history of significant cardiac disease, arrhythmias or angina pectoris. Calcium levels should be monitored in patients receiving this regimen and calcium supplementation should be provided if where hypocalcaemia occurs. Cumulative N/A s References André T, Louvet C, Maindrault-Goebel F, Couteau C, Mabro M, Lotz JP, et al. CPT-11 (Irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer GERCOR Eur J Cancer 35(9): Douillard JY, Cunningham D, Roth AD, Navarro M, James R, Karasek P, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomized trial. The Lancet, March 2000; 355: Tournigand C, André T, Achile E, Lledo G, Flesh M, Mery-Mignard D, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol (2): National Institute for Health and Clinical Excellence. Technology Appraisal 93. Irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer. [internet] accessed 20/01/2011, available at Daniels S. North London Cancer Network, adjustment for cytotoxics in hepatic impairment [internet]. accessed 20/01/2011 available at Daniels S. North London Cancer Network, adjustment forcytotoxics in renal impairment [internet]. accessed 20/01/2011 available at Baxter K, editor. Stockley s Drug Interactions. Pharmaceutical Press; Accessed online on 06/05/09 available at Allwood M, Stanley A, Wright P, editors. The cytotoxics handbook. 4 th ed. Radcliffe Medical Press Summary of Product Characteristics Irinotecan Hydrochloride 20mg/ml concentration for solution for infusion (Hospira) [internet]. accessed 20/01/2011 available from Summary of Product Characteristics Fluorouracil 50mg/ml injection (Hospira) [internet]. accessed 12/01/2011 available from Controlled document Document Number Version Number Page 5 of 6

6 Summary of Product Characteristics Calcium Folinate 10mg/mL injection (Hospira) [internet] accessed 14/01/2011 available from Document title Irinotecan+Modified de Gramont Document number ASWCS11 GI013 Approval date 19/07/2011 Written by Stephen Falk, Consultant Clinical Oncologist BHOC Checked by James Carr, Network Pharmacist, ASWCS Authorised by Jeremy Braybrooke, Chair ASWCS Drugs and Therapeutics Committee Review date 19/07/2013 Document reviewed by Version number 1.2.a Summary of changes ALP/AST changed to ALT/AST Controlled document Document Number Version Number Page 6 of 6