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Systemic Anticancer Therapy Drug Interactions Table

Ref: SACT Interactions Table 4.1 Prepared By J. Allen Checked By S.Williamson/ M.Nagra September 2012 Page 1 of 28

This guide is intended to cover the most common interactions involving Systemic Anticancer therapies, e.g. cytotoxic agents, monoclonal antibodies and targeted therapies.

Whilst every effort has been made to ensure it is a comprehensive resource, there may be some interactions which have been unintentionally omitted. Please interpret the information contained in this guide in addition to clinical information and performance status.

Copyright Northumbria Healthcare NHS Trust & North of England Cancer Network

Version 4.1 October 2012 (Date of Review October 2014)

Any comments on this document to [email protected]

DRUG INTERACTION WITH INFORMATION REFERENCE

Ref: SACT Interactions Table 4.1 Prepared By J. Allen Checked By S.Williamson/ M.Nagra September 2012 Page 2 of 28 DRUG INTERACTION WITH INFORMATION REFERENCE Increased risk of pulmonary toxicity when used in combination Increased risk of agranulocytosis 1 Possibility of reduced absorption of digoxin tablets-switch to Digoxin liquid Patients receiving bleomycin pre-operatively are at greater risk

of developing pulmonary toxicity when oxygen is administered Oxygen at surgery. A reduction in inspired oxygen concentration during 2 operation and post-operatively is recommended

Oral anti diabetic drugs Monitor blood glucose levels, hyperglycaemia in is common 3

Clozapine Increased risk of agranulocytosis 1 Potent CYP3A4 inhibitors and inducers (particularly ketoconazole, Closely monitor as may affect plasma concentration of 1, 3 rifampicin, carbamazepine, bortezomib and St Johns Wart) Clozapine Increased risk of agranulocytosis 1

Cyclophosphamide serum levels may be increased (& active metabolite decreased) if given within 24 hours of 4

Itraconazole and Metronidazole Increase in busulfan toxicity 1,3 Busulfan Ketobemidone Increase in busulfan plasma concentration

Paracetamol May decrease intravenous busulfan plasma levels 4

Phenytoin Increases busulfan clearance

Tioguanine Increased risk of 1

Ref: SACT Interactions Table 4.1 Prepared By J. Allen Checked By S.Williamson/ M.Nagra September 2012 Page 3 of 28 DRUG INTERACTION WITH INFORMATION REFERENCE

Allopurinol Possible decreased efficacy of 5,6

Aluminium and aluminium Small increase in capecitabine toxicity 5 containing antacids

Cimetidine Increased plasma concentration 1

Clozapine Increased risk of agranulocytosis 1

Coumarins Enhanced anticoagulant effect, monitor INR regularly

Erlotinib Could increase plasma concentration of erlotinib

Increased toxicity of capecitabine, maximum tolerated dose is Folinic acid 1,5 reduced.

Decreased rate of capecitabine absorption if administered with Capecitabine Food food. Manufacturers recommend administration within 30 minutes of a meal.

Maximum tolerated dose of capecitabine is decreased by Interferon Alpha interferon alpha 6

Metronidazole Increased toxicity 1

Phenytoin May lead to increased phenytoin levels 5 Potentially fatal combination – leads to increased Sorivudine and analogues fluoropyrimidine activity

Increased photosensitivity risk when topical and 1, 5 temoporfin used concomitantly

Ref: SACT Interactions Table 4.1 Prepared By J. Allen Checked By S.Williamson/ M.Nagra September 2012 Page 4 of 28 DRUG INTERACTION WITH INFORMATION REFERENCE

Allopurinol Potential for increased risk of toxicity when used in combination

Amiodarone Concomitant use may lead to early onset pulmonary toxicity

6 Fluconazole and itraconazole inhibit the metabolism of Azole antifungals cyclophosphamide, leading to increased toxicity

Cyclophosphamide serum levels may be increased (and active Busulfan 5 metabolite decreased) if given within 24 hours of busulfan

Increased renal toxicity when used in combination or in patients Cisplatin 6 who have had prior treatment with cisplatin Cyclophosphamide Clozapine Increased risk of agranulocytosis 1

Digoxin Reduces absorption of digoxin tablets 1

Potentiated by cyclophosphamide Oral antidiabetic drugs -monitor blood glucose levels 7 Increased risk of toxicity when is given with high Pentostatin dose cyclophosphamide

Rifampicin Increased metabolism of cyclophosphamide 6

Suxamethonium Enhances effect of suxamethonium 1

Aldesleukin Avoid concomitant use 8

Dacarbazine Clozapine Increased risk of agranulocytosis 1 Cytochrome P450 (CYP1A1, Darcarbazine is metabolised by cytochrome P450, therefore 8 CYP1A2, and CYP2E1) levels may be altered if co-administered with other substrates

Ref: SACT Interactions Table 4.1 Prepared By J. Allen Checked By S.Williamson/ M.Nagra September 2012 Page 5 of 28 DRUG INTERACTION WITH INFORMATION REFERENCE

Clozapine Increased risk of agranulocytosis 1

Metabolism of clearance altered, may lead to CYP3A inducers and inhibitors 9 increased toxicity or reduced efficacy of docetaxel. Docetaxel Lapatinib Increased risk of 9 Ritonavir Plasma concentration of docetaxel increased 1 Sorafenib Increases the plasma concentration of docetaxel 1

Amphotericin B Marked increase in nephrotoxicity

Reduced absorption of anticonvulsants when administered in Anticonvulsants combination with 10

Anthracyclines and Cardiotoxic Monitor cardiac function as increased risk of cardiotoxicity Channel Blockers Plasma concentration of doxorubicin is increased 1 (verapramil) Doxorubicin Increased risk of neurotoxicity 1

Clozapine Increased risk of agranulocytosis 1

Cytarabine Potential for severe infections and necrosis of intestine CYP3A4 inhibitors Reduction in plasma concentration

Cytochrome P450 inducers and May affect doxorubicin metabolism, leading to increased 10 inhibitors toxicity or decreased efficacy

Possibility of reduced absorption of oral of Digoxin digoxin May increase concentration of metabolites when Epirubicin 11 docetaxel administered immediately after epirubicin Hepatotoxic medication Increased risk of hepatoxicity when used in combination 10 (e.g. 6 – )

Ref: SACT Interactions Table 4.1 Prepared By J. Allen Checked By S.Williamson/ M.Nagra September 2012 Page 6 of 28 DRUG INTERACTION WITH INFORMATION REFERENCE Manufacturer advises to leave at least 24 hours between infusing both drugs as elimination of doxorubicin may be 10 reduced if given within 24 hours of paclitaxel. Doxorubicin (continued) Ritonavir Elevated serum doxorubicin concentration 10

Uric acid lowering agents Doxorubin therapy may lead to an increase in serum 1

Doxorubicin patients should not be actively vaccinated and also Vaccines 1, 10 avoid contact with recently polio vaccinated patients

Cardiotoxic medication Monitor cardiac function as increased risk of cardiotoxicity 11

Ciclosporin Plasma concentration of epirubicin increased by ciclosporin Increases plasma concentration of epirubicin, not explained by 1 Cimetidine CYP activity

Clozapine Increased risk of agranulocytosis

Dexverapamil Possible increased

May increase concentration of epirubicin metabolites when Docetaxel Epirubicin docetaxel administered immediately after epirubicin

Interferon alpha 2b May reduce total clearance of epirubicin

Hepatotoxic medication May affect epirubicin efficacy and toxicity 11, 1

Live vaccines Live vaccines should be avoided Increased risk of toxicity, manufacturers advise at least 24 Paclitaxel hours between infusions if used in combination

Quinine Can accelerate distribution of epirubicin into the tissues

Ref: SACT Interactions Table 4.1 Prepared By J. Allen Checked By S.Williamson/ M.Nagra September 2012 Page 7 of 28 DRUG INTERACTION WITH INFORMATION REFERENCE

Clozapine Increased risk of agranulocytosis

Enzyme inducers Increased plasma concentration

Eribulin Inhibitors of hepatic transport May reduce elimination of eribulin and result in up to three fold proteins increase in plasma concentration 12 Eribulin may inhibit CYP3A4, resulting in increased plasma Substrates of CYP3A4 concentration of the substrate. Avoid concomitant use if substrate has narrow therapeutic range. Plasma concentration of erlotinib potentially reduced by Antacids antacids. Give antacids at least 4 hours before or 2 hours after

Antivirals (bocepravir) Avoid co-administration 1

Clozapine Increased risk of agranulocytosis Enhanced anticoagulant effect, monitor INR regularly as increased risk of bleeding CYP1A2 inhibitors/inducers May alter erlotinib levels 13 CYP3A4 inhibitors/inducers May alter erlotinib levels Erlotinib Avoid concomitant use with cimetidine. Give erlotinib at least 2 H2 antagonists 1 hours before or 10 hours after ranitidine. May reduce plasma concentration-smoking cessation advice 13 should be given. NSAIDS Increased risk of bleeding 1

P-glycoprotein inhibitors May alter erlotinib levels 13 May alter erlotinib levels- manufacturers recommend avoid PPIs 1 concomitant use Statins May increase risk of rhabdomyolysis 13

Ref: SACT Interactions Table 4.1 Prepared By J. Allen Checked By S.Williamson/ M.Nagra September 2012 Page 8 of 28 DRUG INTERACTION WITH INFORMATION REFERENCE

Atovaquone Increases plasma concentration of 1

Etoposide clearance may be increased by phenytoin and Antiepileptics 1, 6

Ciclosporin Increased risk of etoposide toxicity with high dose ciclosporin

Etoposide 1 Clozapine Increased risk of agranulocytosis Coumarins Enhanced anticoagulant effect, monitor INR CYP3A4 Inhibitors may increase side effects and toxicity of CYP3A4 inhibitors etoposide

Myelosuppressive drugs Increases the effect of etoposide and/ or co-administered drug 1, 6 (e.g. 5 – Fluouracil, etc) on bone marrow

May induce the metabolism of etoposide and also antagonise St John’s Wort it’s effects Clozapine Increased risk of agranulocytosis 1

Fludarabine May reduce the efficacy of 6

Increased risk of pulmonary toxicity when these drugs are used Pentostatin 1 in combination, leading to fatalities. Manufacturer advises avoid, can affect bioavailability of active Allopurinol 1 drug

Significant use of cimetidine (4 weeks or more) can increase Cimetidine 14 fluorouracil levels Fluorouracil Possible increase in toxicity (particularly cardiotoxicity) if used Cisplatin 6 in combination

Coumarins Enhanced anticoagulant effect, monitor INR 1

Ref: SACT Interactions Table 4.1 Prepared By J. Allen Checked By S.Williamson/ M.Nagra September 2012 Page 9 of 28 DRUG INTERACTION WITH INFORMATION REFERENCE

Folic Acid Increase in fluorouracil toxicity 6

Leucovorin Can affect availability of active drug Fluorouracil (continued) Increase in fluorouracil toxicity 6,14 Metronidazole Increase in fluorouracil toxicity

Potentially fatal combination – leads to increased Sorivudine and analogues fluoropyrimidine activity

Manufacturer advises avoid concomitant use with phenytoin Antiepileptics and carbamazepine 1 Boceprevir Manufacturer advises to avoid concomitant use

Clozapine Increased risk of agranulocytosis Coumarins Enhanced anticoagulant effect, monitor INR regularly 1, 15 CYP2D6 inhibitors May increase gefitinib levels, monitor for increased toxicity Concomitant administration may alter levels of substrate, CYP2D6 substrates monitor if substrate with narrow therapeutic index Gefitinib CYP3A4 inducers May decrease gefitinib levels and therefore efficacy 15

CYP3A4 inhibitors May increase gefitinib levels, monitor for increased toxicity

High dose short acting antacids May reduce gefitinib levels and therefore efficacy Ranitidine May reduce gefitinib levels and therefore efficacy 15 Rifampicin Plasma concentration reduced-avoid concomitant use

St Johns Wort Manufacturer advises to avoid concomitant use 1

Ref: SACT Interactions Table 4.1 Prepared By J. Allen Checked By S.Williamson/ M.Nagra September 2012 Page 10 of 28 DRUG INTERACTION WITH INFORMATION REFERENCE

Clozapine Increased risk of agranulocytosis 1 Coumarins Enhances anticoagulant effect. Monitor INR closely 1 Yellow fever and other Live Increased risk of systemic disease 16 attenuated vaccines administered immediately after gemcitabine may Platinum based 6 cause increased severity of Radiotherapy Gemcitabine may cause radiosensitisation when given 16 concurrently with (or within 7 days of) radiotherapy Antivirals (Boceprevir) Avoid concomitant use with imatinib

1 Clozapine Increased risk of agranulocytosis Monitor INR, SPC states patients should be treated with low Coumarins molecular weight heparin or standard heparin CYP3A4 inducers Lower plasma concentration of imatinib, reducing efficacy CYP3A4 inhibitors Increase plasma concentration of imatinib, monitor for toxicity Imatinib may alter the plasma concentration of substrates so CYP3A4 substrates caution should be used if they have a narrow therapeutic window, such as ciclosporin. 17 Enzyme inducing antiepileptics May reduce plasma concentration of imatinib

Imatinib L- Increased risk of hepatotoxicity

Plasma exposure to may be decreased when Levothyroxine used in conjunction with imatinib. Monitor thyroid function tests. Caution should be used if co-administering high dose imatinib Paracetamol and paracetamol Plasma concentration of imatinib reduced, avoid concomitant Rifampicin use Statins Plasma concentration is increased 1 Plasma concentration of imatinib reduced, avoid concomitant St Johns Wort use

Ref: SACT Interactions Table 4.1 Prepared By J. Allen Checked By S.Williamson/ M.Nagra September 2012 Page 11 of 28 DRUG INTERACTION WITH INFORMATION REFERENCE

Clearance of increased by phenytoin and Antiepileptics phenobarbital. valproate may decrease clearance of 6 irinotecan active metabolite. Metabolism of irinotecan inhibited by atazanavir. Antivirals (Atazanavir) 1 Increased risk of toxicity May possibly reduce tolerated dose of irinotecan and result in increased incidence of side effects Clozapine Increased risk of agranulocytosis 18 CYP3A4 inducing antiepileptics May reduce irinotecan plasma levels

CYP3A4 inducers/inhibitors May affect irinotecan levels by altering metabolism

Ketoconazole Increases concentration of irinotecan active metabolite 1

Plasma concentration of irinotecan active metabolite increased Irinotecan Lapatinib 1 by lapatinib

Irinotecan has anticholinesterase activity and may prolong neuromuscular blocking effects of suxamethonium, and may Neuromuscular blocking agents 18 also antagonise neuromuscular blockade of non-depolarising drugs e.g. pancuronium, rocuronium

Physotigmine May inhibit irinotecan activation 6

Sorafenib Plasma concentration of irinotecan is increased 1

St John’s Wort Increases metabolism of irinotecan, reducing plasma levels 1,18

Vinorelbine Affects metabolism of irinotecan 6

Ref: SACT Interactions Table 4.1 Prepared By J. Allen Checked By S.Williamson/ M.Nagra September 2012 Page 12 of 28 DRUG INTERACTION WITH INFORMATION REFERENCE

Antibacterials e.g. rifabutin, Manufacturer advises avoid concomitant use rifampicin, telithromycin 1

Antiepileptics Avoid concomitant use with phenytoin and carbamazepine Avoid concomitant use with ketoconazole, itraconazole, Antifungals posaconazole and voriconazole Antivirals Avoid concomitant use with boceprevir, ritonavir and saquinavir 1

Clozapine Increased risk of agranulocytosis Manufacturer advises avoid concomitant use with substrates CYP2C8 substrates e.g. repaglinide that have a narrow therapeutic window CYP3A4 inducers May decrease lapatinib levels and therefore efficacy May increase plasma laptanib levels. Co-administration with CYP3A4 inhibitors 19 strong inhibitors should be avoided. Docetaxel Increased risk of neutropenia Lapatinib Food Bioavailability of lapatinib may be affected by food Grapefruit Juice Manufacturer advises avoid concomitant use 1

Irinotecan May increase levels of active metabolite of irinotecan Increase in diarrhoea and neutropenia observed due to Paclitaxel increased plasma concentration of paclitaxel 19 Co-administration may increase plasma concentration of P-glycoprotein substrates substrate drug. Manufacturer advices caution with substrates that have a narrow therapeutic window Pimozide Avoid concomitant use 1 histamine and H2 Proton Pump Co-administration may result in reduced laptanib levels 19 Inhibitors Repaglinide (Substrates of CYP2C8) Manufacturer advises to avoid concomitant use 1 St Johns Wort

Ref: SACT Interactions Table 4.1 Prepared By J. Allen Checked By S.Williamson/ M.Nagra September 2012 Page 13 of 28 DRUG INTERACTION WITH INFORMATION REFERENCE

Cimetidine May potentiate bone marrow toxicity 1, 20

Clozapine Increased risk of agraulocytosis 1 Digoxin Reduced absorption of digoxin tablets-switch to liquid May lead to increased elimination and reduced efficacy of Pre- treatment of phenobarbital lomustine 20 May potentiate bone marrow toxicity

Cardiac glycosides (digoxin) Reduced absorption 1

May increase risk of impaired renal function. Increased risk of Ciclosporin 1, 21 nephrotoxicity

Cimetidine Cimetidine may reduce bioavailability of 6

Clozapine Increased risk of agraulocytosis 1 Melphalan Food Absorption of melphalan can be reduced by food 6 Interferon Alfa May increase cytotoxicity due to interferon induced fever

Live vaccines Manufacturer advises to avoid concomitant use 21 May lead to haemorrhagic enterocolitis when used in Nalidixic acid combination with high dose intravenous melphalan

Possibility of reduced absorption of phenytoin ?? (not listed in Phenytoin 1 BNF or SPC?)

Ref: SACT Interactions Table 4.1 Prepared By J. Allen Checked By S.Williamson/ M.Nagra September 2012 Page 14 of 28 DRUG INTERACTION WITH INFORMATION REFERENCE

Increases methotrexate concentration and may increase risk Acitretin 22 hepatotoxicity

Amphotericin B May delay clearance of methotrexate 6 Antibacterials e.g. co-trimoxazole, sulfamethoxazole, Increased risk of haematological toxicity .

Aminoglycosides Aminoglycosides may reduce GI absorption

Ciprofloxacin Ciprofloxacin may increase methotrexate toxicity

Reduced renal clearance of methotrexate, GI toxicity may Antibiotics occur

Antimalarials effect increased by Methotrexate Avoid as methotrexate efficacy may reduce due to interaction 1, 22 with methylxanthines at receptors Ciclosporin Increased risk of toxicity

Cisplatin Increased risk of pulmonary toxicity May affect methotrexate transport function of renal tubules, Chloramphenicol increasing methotrexate concentration and toxicity

Clozapine Increased risk of agranulocytosis

Increases the non – renal elimination of methotrexate by Colestyramine interrupting the enterohepatic circulation antagonists e.g. Concomitant use should be avoided trimethoprim, cotrimoxazole Hepatotoxic medication Concomitant use should be avoided. Increased hepatotoxicity

Leflunomide Increased risk of toxicity 22

Live vaccines Manufacturer advises to avoid concomitant use

Ref: SACT Interactions Table 4.1 Prepared By J. Allen Checked By S.Williamson/ M.Nagra September 2012 Page 15 of 28 DRUG INTERACTION WITH INFORMATION REFERENCE Antifolate effect of methotrexate increased by nitrous oxide. Nitrous Oxide 1 Avoid concomitant use. NSAIDs

Oral hypoglycaemics May affect methotrexate transport function of renal tubules, 22 increasing methotrexate concentration and toxicity

Sulphonamides

Tetracyclines Methotrexate (continued) Proton pump inhibitors (omeprazole) Increased risk of toxicity 1 Radiotherapy Increased risk of soft tissue or bone necrosis Methotrexate may possibly increase plasma level of Theophylline theophylline 1 May affect methotrexate transport function of renal tubules, Thiazide increasing methotrexate concentration and toxicity preparations including folic May alter response to methotrexate 22 acid Plasma concentration of paclitaxel increased by nelfinavir and Antivirals 1 ritonavir Manufacturer recommends administration of paclitaxel before 23 Cisplatin cisplatin, due to increased risk of toxicity and renal failure if

administered post cisplatin Clozapine Increased risk of agranulocytosis

Digoxin Reduced absorption of digoxin tablets-switch to liquid 1 Manufacturer advises to leave at least 24 hours between Paclitaxel Doxorubicin infusing both drugs as elimination of doxorubicin may be reduced if given within 24 hours of paclitaxel.

CYP2C8 inhibitors or inducers Use with caution – may alter metabolism of paclitaxel 23 CYP3A4 inhibitors/inducers

Ref: SACT Interactions Table 4.1 Prepared By J. Allen Checked By S.Williamson/ M.Nagra September 2012 Page 16 of 28 DRUG INTERACTION WITH INFORMATION REFERENCE

Lapatinib Increased risk of neutropenia 1 Paclitaxel (continued) Nelfinavir and ritonavir (and other May reduce paclitaxel clearance leading to increased toxicity 23 protease inhibitors)

Phenytoin May reduce absorption of phenytoin when used concomitantly 1

May reduce clearance of when high doses of aspirin (>1.3g/day) administered concomitantly 24

Clozapine Increased risk of agranulocytosis

Digoxin Reduced absorption of digoxin tablets-switch to liquid?? 1

Possibly reduce clearance of pemetrexed, manufacturer Drugs secreted by renal tubules e.g. advises use in combination with caution and with monitoring of penicillin, probenecid creatinine clearance 24 Possibly reduce clearance of pemetrexed, manufacturer Pemetrexed Nephrotoxic drugs advises use in combination with caution and with monitoring of creatinine clearance High doses (e.g ibuprofen > 1600mg daily or asprin > 1.3g daily) may decrease pemetrexed elimination. Manufacturer advises in patients with mild to moderate renal insufficiency NSAIDs 6, 24 treatment with longer acting NSAIDs such as piroxicam should be interrupted for at least 5 days prior to, on the day of, and at least 2 days following pemetrexed administration

Antifolate effect of pemetrexed is increased by concomitant Pyrimethamine 1 use with pyrimethamine

Yellow fever and Live attenuated Risk of fatal generalised vaccinale disease vaccines

Ref: SACT Interactions Table 4.1 Prepared By J. Allen Checked By S.Williamson/ M.Nagra September 2012 Page 17 of 28 DRUG INTERACTION WITH INFORMATION REFERENCE Aldesleukin Manufacturer advises to avoid concomitant use with cisplatin 1

Allopurinol (and other drugs which affect serum uric acid levels e.g. May require dosage adjustment as cisplatin can increase 25 , probenecid or serum uric acid concentration ) Carboplatin may form a black precipitate in the presence of Aluminium 26 aluminium Increased risk of nephro- and ototoxicity when platinum drugs Antibacterials 1 given with aminoglycosides or polymixins May reduce therapeutic levels of phenytoin. Initiation of treatment with phenytoin when a patient is on cisplatin is Antiepileptics contra-indicated. For patients who are already established on 25 phenytoin, monitoring of levels is required.

Platinum compounds May mask the symptoms of ototoxicity May increase incidence of nephrotoxicity when given with Carboplatin Antihypertensives cisplatin, (specifically , hydralazine, diazoxide, 1, 25 Cisplatin propanolol) Can lead to Raynaud phenomenon when given with cisplatin, 1, 25 Bleomycin and increase risk of pulmonary toxicity

Chelating agents (e.g. penicillamine) Diminishes effectiveness of cisplatin 1, 25

Ciclosporin Excessive immunosuppression, with risk of lymphoproliferation 26

Clozapine Increased risk of agranulocytosis 1 Increased risk of nephro- and ototoxicity when given with Diuretics platinum compounds Greatly increased incidence of neurotoxic effects compared to Docetaxel each individual drug 25 May increase risk of nephro- and ototoxicity when used in combination

Ref: SACT Interactions Table 4.1 Prepared By J. Allen Checked By S.Williamson/ M.Nagra September 2012 Page 18 of 28 DRUG INTERACTION WITH INFORMATION REFERENCE

Monitoring of levels recommended when a combination Lithium of lithium and cisplatin are used.

Yellow fever vaccine Risk of fatal systemic vaccinal disease 26

Live vaccines Manufacturer advises to avoid concomitant use?? 25

Methotrexate Increased risk of pulmonary toxicity 1 Nephrotoxic drugs May increase risk of toxicity due to changes in renal clearance 1, 25 Platinum compounds Ototoxic drugs May increase risk of toxicity due to changes in renal clearance (continued) 25 May reduce clearance of cisplatin when cisplatin treatment Paclitaxel Carboplatin given prior to paclitaxel, increasing neurotoxicity Cisplatin May increase time to response when used in combination 25 Oxaliplatin If either cisplatin or carboplatin is given on day 1 of the dosing, a lower dose of each agent must be given to Topotecan improve tolerability compared to the dose of each agent which 27 can be given if the platinum agent is given on day 5 of the topotecan dosing. Can lead to Raynaud phenomenon and increased plasma Vinblastine levels of vinblastine when given with cisplatin 25 Regular monitoring of INR recommended Ciclosporin A May increase plasma topotecan levels

If either cisplatin or carboplatin is given on day 1 of the topotecan dosing, a lower dose of each agent must be given to Cisplatin/Carboplatin improve tolerability compared to the dose of each agent which 27 can be given if the platinum agent is given on day 5 of the Topotecan topotecan dosing.

Inhibitors of ABCB1 and ABCG2 (P- May increase plasma topotecan levels glycoprotein inhibitors) May increase phenytoin clearance and reduce levels when Phenytoin 6 used concomitantly

Ref: SACT Interactions Table 4.1 Prepared By J. Allen Checked By S.Williamson/ M.Nagra September 2012 Page 19 of 28 DRUG INTERACTION WITH INFORMATION REFERENCE Levels, particularly of phenytoin, may be reduced by regimes Antiepileptics 28 including vinblastine and Antivrals (ritonavir) Plasma concentration of vinblastine is increased 1 Antifungals (Itraconazole, Inhibits hepatic metabolism of vinblastine and vincristine, 6, 28,30 Posaconazole, Voriconazole) leading to increased neurotoxicity. Allopurinol May increase bone marrow depression with vincristine 29 May lead to increased neurotoxicity when given with vincristine. Asparaginase It is recommended that vincristine should be administered 12 to 6 24 hours before asparaginase Can lead to raynaud phenomenon and gangrene when given Bleomycin concomitantly with vinblastine. May also lead to serious 6, 28 cardiovascular toxicity. Increased risk of immunosuppression and lymphoproliferation Ciclosporin 31 when given in conjuction with Can lead to Raynaud Phenomenon and increased plasma Cisplatin 25 levels of vinca alkaloids when given concomitantly. Vinca Alkaloids Clarithromycin Increased risk of neutropenia with vinorelbine 1 Clozapine Increased risk of agranulocytosis 1 Vinblastine May increase metabolism of vinca alkaloids, leading to reduced CYP3A4 inducers 29, 31 Vincristine efficacy May inhibit metabolism of vinca alkaloids, leading to increased CYP3A4 inhibitors 29 Vinorelbine incidence of neuromuscular side effects Vincristine - possibility of reduced absorption of digoxin tablets- Digoxin 1 switch to liquid Drugs which act on the peripheral May have an additive neurotoxic effect when given with 29 nervous system vincristine Erythromycin Can Increase vinblastine toxicity 6, 28

Isoniazid May increase bone marrow depression with vincristine 6, 29

L-asparaginase Vincristine should be given 12 to 24 hours before administration of L-asparaginase in order to minimise toxicity, 29 since administering L-asparaginase first may reduce hepatic clearance of vincristine. Live attenuatedvaccines Manufacturer of vinorelbine advises to avoid live vaccines 31

Ref: SACT Interactions Table 4.1 Prepared By J. Allen Checked By S.Williamson/ M.Nagra September 2012 Page 20 of 28 DRUG INTERACTION WITH INFORMATION REFERENCE Methotrexate Vincristine increases cellular uptake of methotrexate. 29 May result in respiratory distress and pulmonary infiltration Mitomycin 6, 28, 29, 30 when given with vinca alkaloids Nifedipine Reduces the clearance of vincristine 6 May alter vinorelbine levels as it is a p-glycoprotein substrate. P-glycoprotein inhibitors/inducers 31 Manufacturer advises caution when used in combination. Pyridoxine May increase bone marrow depression with vincristine Vincristine and vindesine treatment should be delayed until 29, 30 Radiotherapy radiotherapy is finished when using portals in the Increased risk of immunosuppression and lymphoproliferation Tacrolimus/ Ciclosporin 31 when given in conjuction with vinorelbine

Ref: SACT Interactions Table 4.1 Prepared By J. Allen Checked By S.Williamson/ M.Nagra September 2012 Page 21 of 28

MONOCLONAL INTERACTION WITH INFORMATION REFERENCE ANTIBODY Manufacturer advises that three weeks should be left between Chemotherapy administration of chemotherapy and alemtuzumab Increased neuro- toxicity due to decrease of hepatic Itraconazole 32 Alemtuzumab metabolism

Avoid concomitant use – risk of generalised vaccine disease – Live attenuated vaccines possibly fatal Risk of toxicity enhancement or loss of efficacy of cytotoxic Phenytoin 32 drug

Trial data suggests the combination of Anti-EGFR monoclonal Anti-EGFR monoclonal antibodies antibody, plus bevacizumab and chemotherapy leads to (e.g. cetuximab/panitumumab) decreased performance status and increased toxicity

Increased risk of infection and neutropenia, including severe Platinum based chemotherapy neutropenia, when used in combination Bevacizumab 33 Some trial data to suggest increased risk of microangiopathic Sunitinib haemolytic anaemia when used in combination. Reversible upon discontinuation of both drugs

Increased risk of infection and neutropenia, including severe based chemotherapy neutropenia, when used in combination Trial data suggests the combination of Anti-EGFR monoclonal Bevacizumab antibody (cetuximab), plus bevacizumab and chemotherapy leads to decreased performance status and increased toxicity Increased risk of cardiac ischaemia, myocardial infarction and Fluoropyrimidines Cetuximab palmar-plantar erythema 34 Increased risk of infection and neutropenia, including severe Platinum based chemotherapy neutropenia, when used in combination XELOX (capecitabine and Increased frequency of severe diarrhoea oxaliplatin)

Ref: SACT Interactions Table 4.1 Prepared By J. Allen Checked By S.Williamson/ M.Nagra September 2012 Page 22 of 28 MONOCLONAL INTERACTION WITH INFORMATION REFERENCE ANTIBODY Abatacept Avoid concomitant use 1, 35 Anakinra Infliximab Reduced formation of antibodies against infliximab and Immunomodulators 35 increased infliximab plasma concentration Live vaccines Avoid concomitant use 1, 35

Trial data suggests the combination of Anti-EGFR monoclonal Bevacizumab antibody (panitumumab), plus bevacizumab and chemotherapy 34,36 leads to decreased performance status and increased toxicity

IFL chemotherapy (bolus 5-fluorouracil (500 mg/m2), Panitumumab Increased risk of severe diarrhoea 36 leucovorin (20 mg/m2) and irinotecan (125 mg/m2)

Contraindicated in patients with mutant KRAS expression or Oxaliplatin containing regimes where KRAS status is unknown, due to decreased 36 performance status and reduced overall survival

Rituximab Immunomodulators Increased risk of infection when used in combination 37 Live vaccines Avoid concomitant use 1

Doses of medication metabolised by these isoenzymes may Tocilizumab Substrates of CYP450 3A4, 1A2 or need to be increased to maintain the same therapeutic effect 38 2C9 achieved prior to tocilizumab treatment

Cardiotoxic medication Increased risk of cardiotoxicity Trastuzumab 39 No formal interaction studies Manufacturer cannot rule out risk of interaction with other performed medication

Ref: SACT Interactions Table 4.1 Prepared By J. Allen Checked By S.Williamson/ M.Nagra September 2012 Page 23 of 28 Examples of enzyme inducers/ inhibitors

SUBSTRATES INHIBITORS INDUCERS CYP1A2 acetaminophen mexiletine amiodarone methoxsalen carbamazepine cimetidine mexiletine charbroiled food caffeine naproxen ciprofloxacin nalidixic acid lansoprazole norethindrone omeprazole clarithromycin norfloxacin phenobarbital diltiazem omeprazole phenytoin clozapine propafenone enoxacin oral contraceptives cyclobenzaprine erythromycin rifampin riluzole ethinyl tacrine ritonavir ropinirole smoking estradiol ropivacaine troleandomycin St John’s wort flutamide tacrine ketoconazole zileuton fluvoxamine theophylline verapamil (R)-warfarin levobupivacaine zileuton CYP2C9 amitriptyline mefenamic acid amiodarone ketoconazole aprepitant carvedilol meloxicam chloramphenicol leflunomide carbamazepine cimetidine lovastatin phenobarbital clomipramine naproxen clopidogrel metronidazole phenytoin desogestrel nateglinide cotrimoxazole modafinil primidone diazepam omeprazole delavirdine omeprazole rifampin diclofenac phenytoin disulfiram paroxetine rifapentine piroxicam efavirenz rosiglitazone sulfonamides flurbiprofen sildenafil fluconazole ticlopidine fluvastatin sulfamethoxazole fluorouracil voriconazole formoterol tolbutamide fluoxetine zafirlukast glimepiride torsemide fluvastatin glipizide valdecoxib fluvoxamine glyburide valsartan gemfibrozil ibuprofen voriconazole imatinib imipramine (S)-warfarin isoniazid indomethacin zafirlukast itraconazole irbesartan & zileuton

Ref: SACT Interactions Table 4.1 Prepared By J. Allen Checked By S.Williamson/ M.Nagra September 2012 Page 24 of 28 SUBSTRATES INHIBITORS INDUCERS CYP2C19 amitriptyline nelfinavir citalopram letrozole carbamazepine nilutamide delavirdine modafinil norethindrone omeprazole efavirenz omeprazole phenobarbital citalopram pantoprazole felbamate oxcarbazepine phenytoin clomipramine pentamidine fluconazole paroxetine prednisone cyclophosphamide phenytoin fluoxetine sertraline rifampin desipramine fluvastatin telmisartan diazepam proguanil fluvoxamine ticlopidine esomeprazole propranolol indomethacin topiramate formoterol rabeprazole isoniazid voriconazole hexobarbital ketoconazole imipramine thioridazine indomethacin tolbutamide lansoprazole voriconazole mephobarbital (R)-warfarin CYP2D6 amitriptyline imipramine amiodarone paroxetine carbamazepine amphetamine lidocaine perphenazine celecoxib propafenone phenobarbital bisoprolol meperidine cimetidine propoxyphene phenytoin carvedilol methoxyamphetamin citalopram quinacrine primidone cevimeline e clomipramine quinidine rifampin metoprolol cocaine ranitidine ritonavir clozapine mexiletine desipramine ritonavir St John’s wort codeine nortriptyline sertraline cyclobenzaprine olanzapine fluoxetine terbinafine desipramine ondansetron fluphenazine thioridazine dexfenfluramine halofantrine donepezil propranolol haloperidol imatinib encainide levomepromazine fenfluramine thioridazine methadone fentanyl timolol moclobemide flecainide tolterodine norfluoxetine fluphenazine tramadol

Ref: SACT Interactions Table 4.1 Prepared By J. Allen Checked By S.Williamson/ M.Nagra September 2012 Page 25 of 28 SUBSTRATES INHIBITORS INDUCERS alfentanil mometasone acitretin metronidazole aminoglutethimide CYP3A4 almotriptan montelukast amiodarone methylprednisolone aprepitant nateglinide amprenavir miconazole carbamazepine amitriptyline aprepitant mifepristone amiodarone nelfinavir cimetidine nefazodone efavirenz nevirapine ciprofloxacin nelfinavir ethosuximide amprenavir nicardipine clarithromycin nicardipine garlic supplements aprepitant nifedipine cyclosporine nifedipine glucocorticoids nimodipine danazol norethindrone glutethimide bepridil nisoldipine delavirdine norfloxacin griseofulvin nitrendipine diltiazem norfluoxetine modafinil bromocriptine norethindrone diethyldithiocarbama oxiconazole nafcillin budesonide omeprazole te prednisone nevirapine buprenorphine ondansetron efavirenz quinine oxcarbazepine cilostazol oral contraceptives erythromycin ritonavir phenobarbital cisapride sertraline ethinyl estradiol roxithromycin phenytoin delavirdine sibutramine fluconazole saquinavir primidone desogestrel temazepam fluoxetine sertraline rifabutin dexamethasone testosterone fluvoxamine Synercid rifampin dextromethorphan gestodene troleandomycin rifapentine diazepam tolterodine grapefruit verapamil St John’s wort dihydroergotamine toremifene voriconazole diltiazem tramadol imatinib zafirlukast disopyramide isoniazid zileuton docetaxel triazolam itraconazole dofetilide ketoconazole valdecoxib donepezil verapamil doxorubicin vinblastine dronabinol vincristine dutasteride vinorelbine efavirenz voriconazole ergotamine (R)-warfarin etoposide zaleplon exemestane zileuton felodipine fentanyl zolpidem

Ref: SACT Interactions Table 4.1 Prepared By J. Allen Checked By S.Williamson/ M.Nagra September 2012 Page 26 of 28 SUBSTRATES INHIBITORS INDUCERS CYP2C8 amiodarone repaglinide anastrozole carbamazepine CYP3A4 benzphetamine retinoic acid gemfibrozil phenobarbital carbamazepine nicardipine rifabutin docetaxel rosiglitazone rifampicin fluvastatin tolbutamide sulfaphenazole rifampin isotretinoin sulfinpyrazone paclitaxel verapamil trimethoprim phenytoin warfarin pioglitazone zopiclone

References:

1. Joint Formulary Committee. British National Formulary. 63rd ed. London: BMJ Group and Pharmaceutical Press; 2012 2. Kyowa Hakko Kirin UK Ltd. Summary of Product Characteristics- Bleomycin. 2009 3. Janssen-Cilag Ltd. Summary of Product Characteristics- Bortezomib. 2012 4. Pierre Fabre Limited. Summary of Product Characteristics- Busulfan. 2011 5. Roche Products Limited. Summary of Product Characteristics-Capecitabine. 2011 6. Baxter, K. ed., Stockley’s Drug Interactions. Seventh Edition. London: Pharmaceutical Press 7. Pharmacia Limited. Summary of Product Characeteristics-Cyclophosphamide. 2012 8. Medac GmbH. Summary of Product Characteristics-. 2011. 9. Actavis UK Ltd. Summary of Product Characteristics-Docetaxel. 2011 10. Actavis UK Ltd. Summary of Product Characteristics-Doxorubicin. 2012 11. Hospira UK Ltd. Summary of Product Characteristics-Epirubicin. 2011 12. Eisai Ltd. Summary of Product Characteristics-Eribulin. 2012 13. Roche Products Limited. Summary of Product Characteristics-Erlotinib. 2012 14. Hospira UK Ltd. Summary of Product Characteristics-Fluorouracil. 2011 15. AstraZeneca UK Limited. Summary of Product Characteristics-Gefitinib. 2012 16. Hospira UK Ltd. Summary of Product Characteristics-Gemcitabine. 2010

Ref: SACT Interactions Table 4.1 Prepared By J. Allen Checked By S.Williamson/ M.Nagra September 2012 Page 27 of 28 17. Novartis Pharmaceuticals UK Ltd. Summary of Product Characteristics-Imatinib. 2012 18. Actavis UK Ltd. Summary of Product Characteristics-Irinotecan. 2010 19. GlaxoSmithKline UK. Summary of Product Characteristics-Lapatinib. 2012 20. Medac GmbH. Summary of Product Characteristics-Lomustine. 2007 21. Aspen. Summary of Product Characteristics-Melphalan. 2012 22. Pharmacia Limited. Summary of Product Characteristics-Methotrexate. 2012 23. Hospira UK Ltd. Summary of Product Characteristics-Paclitaxel.2012 24. Eli Lilly and Company Limited. Summary of Product Characteristics-Pemetrexed.2012 25. Hospira UK Ltd. Summary of Product Characteristics-Carboplatin. 2009 26. Accord Healthcare Limited. Summary of Product Characteristics-Cisplatin. 2012 27. sanofi-aventis. Summary of Product Characteristics-Oxaliplatin. 2012 28. Hospira UK Ltd. Summary of Product Characteristics-Vinblastine. 2009. 29. Hospira UK Ltd. Summary of Product Characteristics-Vincristine. 2009 30. Genus Pharma. Summary of Product Characteristics-Vindesine. 2008 31. Pierre Fabre Limited. Summary of Product Characteristics-Vinorelbine. 2011 32. Genzyme Therapeutics. Summary of Product Characteristics- Alemtuzumab. 2011 33. Roche Products Limited. Summary of Product Characteristics-Bevacizumab. 2012 34. Merck Serono. Summary of Product Characteristics-Cetuximab. 2012 35. Merck Sharp & Dohme Limited. Summary of Product Characteristics-Infliximab.2012 36. Amgen Ltd. Summary of Product Characteristics- Panitumumab. 2012 37. Roche Products Limited. Summary of Product Characteristics- Rituximab. 2012 38. Roche Products Limited. Summary of Product Characteristics- Tocilizumab. 2012 39. Roche Products Limited. Summary of Product Characteristics-Trastuzumab. 2012

Ref: SACT Interactions Table 4.1 Prepared By J. Allen Checked By S.Williamson/ M.Nagra September 2012 Page 28 of 28