Systemic Anticancer Therapy Drug Interactions Table 1
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 1 June 2015 (Date of Review June 2018) Any comments on this document to jennifer.allen@nhct.nhs.uk 2
Drug Interacting Drug/Agent Information& Advice Reference BRCP substrates Afatinib may increase the bioavailability of BRCP substrates e.g. rosuvastatin& sulfasalazine Afatinib Food Reduction in exposure to Afatinib by 50% if given with food - administer Afatinib without food Increased plasma concentration of Afatinib. Use SPC (1) Strong P-glycoprotein inhibitors staggered dosing, preferably 6 hours or 12 hours apart from Afatinib Strong P-glycoprotein inducers May reduce plasma concentration of Afatinib. Aflibercept No information listed in SPC or BNF Amsacrine No information listed in SPC or BNF Axitinib Azacitidine Bendamustine SPC (1) CYP3A4 inducers Strong inducers may increase Axitinib metabolism, leading to decreased plasma concentration Adjust dose accordingly Strong inhibitors may reduce Axitinib metabolism, CYP3A4 inhibitors leading to increased plasma concentration Adjust dose accordingly CYP1A2/CYP2C19 inhibitors CYP1A2 substrates Grapefruit Juice Ciclosporin Strong inhibitors may reduce Axitinib metabolism, leading to increased plasma concentration Caution is advised Co-administration with Axitinib may result in increased concentration of the substrate Plasma concentration of Axitinib possibly increased by grapefruit juice No information listed in SPC or BNF Potential for excessive immunosuppression with risk of lymphoproliferation SPC (3) SPC (4) 3
Bendamustine Continued Bexarotene CYP1A2 inhibitors Potential for interaction with CYP1A2 inhibitors Tacrolimus Potential for excessive immunosuppression with risk of lymphoproliferation SPC (4) Live vaccines Increased risk of infection post vaccination, manufacturer advises avoid CA125 assay CA125 assay values in patients with ovarian cancer may be accentuated SPC (5) CYP3A4 substrates CYP3A4 inducers CYP3A4 metabolism Food Gemfibrozil May increase bexarotene plasma levels. Use caution when co-administering with substrates with a narrow therapeutic window May reduce bexarotene plasma levels Repeated administration of bexarotene may result in an auto-induction of its own metabolism and, particularly at dose levels greater than 300 mg/m 2 /day, may increase the rate of metabolism and reduce plasma concentrations of other substances metabolised by CYP3A4 Recommended that capsules are taken with food Plasma concentration of bexarotene increased by gemfibrozil avoid concomitant use SPC (5) Bleomycin Brentuximab vedotin Increased risk of pulmonary toxicity when brentuximab vedotin given with bleomycin avoid concomitant use 4
Bleomycin continued Bortezomib Busulfan Cabazitaxel Cisplatin Increased risk of pulmonary toxicity when used in combination SPC (6) Digoxin Possibility of reduced absorption of digoxin tablets Oxygen Patients receiving bleomycin pre-operatively are at greater risk of developing pulmonary toxicity when oxygen is administered at surgery. A reduction in inspired oxygen concentration during operation and post-operatively is recommended SPC (6). Oral anti diabetic drugs Monitor blood glucose levels, hyperglycaemia may commonly occur SPC (7) Potent CYP3A4 inhibitors and inducers Closely monitor as may affect plasma concentration of bortezomib SPC (7) Cyclophosphamide serum levels may be increased (& Cyclophosphamide active metabolite decreased) if given within 24 hours SPC (8) of busulfan Itraconazole and Metronidazole Increase in busulfan toxicity Ketobemidone Increase in busulfan plasma concentration Live vaccines Increased risk of infection post vaccination, SPC (8) manufacturer advises avoid Paracetamol May decrease intravenous busulfan plasma levels Phenytoin Plasma concentration of busulfan possibly reduced Tioguanine Increased risk of hepatotoxicity Potent CYP3A4 inhibitors and inducers Closely monitor as may affect plasma concentration of cabazitaxel SPC (9) Live vaccines Increased risk of infection post vaccination, SPC (9) 5
Cabazitaxel continued Capecitabine OATP1B1 substrates St Johns Wort Allopurinol Aluminium and aluminium containing antacids Cimetidine Coumarins CYP2C9 substrates Digoxin Erlotinib Filgrastim Folinic acid Food Interferon Alpha Metronidazole Phenytoin manufacturer advises avoid Manufacturer advises leave 12 hours before cabazitaxel infusion and at least 3 hours after before administering OATP1B1 substrates e.g. statins, valsartan, repaglinide Avoid concomitant use Possible decreased efficacy of capecitabine SPC (9) SPC Small increase in capecitabine toxicity SPC (10) Increased plasma concentration of capecitabine Enhanced anticoagulant effect, monitor INR regularly Use caution when co-administering capecitabine and SPC (10) CYP2C9 substrates Absorption of digoxin possibly reduced Potential increase in plasma concentration of erlotinib Potential for exacerbation of neutropenia when given in combination Increased toxicity of capecitabine, maximum tolerated dose is reduced Decreased rate of capecitabine absorption if administered with food. Manufacturers recommend SPC (10) administration within 30 minutes of a meal Maximum tolerated dose of capecitabine is decreased by interferon alpha Increased toxicity of capecitabine due to reduced metabolism Capecitabine may inhibit metabolism of phenytoin, 6
Capecitabine continued Carmustine Chlorambucil Cladribine Clofarabine leading to increased risk of toxicity Radiotherapy Maximum dose of capecitabine should be adjusted when given in combination with radiotherapy Sorivudine and analogues Potentially fatal combination leads to increase fluoropyrimidine activity SPC (10) Temoporfin Increased photosensitivity risk when topical fluorouracil and tempoporfin used concomitantly Cimetidine Increased potential for myelosuppresion when used in combination Digoxin Absorption of digoxin possibly reduced Phenytoin Absorption of phenytoin possibly reduced Live vaccines Increased risk of infection post vaccination, manufacturer advises avoid Purine nucleoside analogues e.g. Increased cytotoxicity of chlorambucil (however SPC (11) pentostatin, fludarabine, cladribine clinical significance unknown) Purine nucleoside analogues e.g. Co-administration is not advisable due to potential for pentostatin, fludarabine, cladribine cross-resistance SPC (12) Co-administration leads to increased risk of severe Corticosteroids infection Myelosuppressive agents Products undergoing intracellular phosphorylation e.g. antiviral drugs, inhibitors of adenosine uptake Products which can cause renal toxicity Products which can cause hepatic toxicity Products which can affect blood pressure Increase in toxicity and risk of myelosuppression if used concomitantly Interactions with cladribine are expected and concomitant use should be avoided Avoid concomitant use Avoid concomitant use Monitor closely when used in combination SPC (12) SPC (13) 7
Crizotinib and cardiac function Analgesics Antibacterials e.g. clarithromycin, rifampicin Antiepileptics e.g. phenytoin, carbamazepine, phenobarbital Caution advised with alfentanil and fentanyl May affect Crizotinib plasma concentrations Plasma concentration of Crizotinib possibly reduced SPC (14) Antifungals e.g. itraconazole, voriconazole Plasma concentration of Crizotinib possibly increased Antivirals e.g. atazanavir, indinavir, ritonavir, saquinavir Beta blockers Calcium channel blockers Ciclosporin Clonidine Digoxin Ergot Alkaloids Grapefruit juice Mefloquine Midazolam OCT1/OCT2 substrates e.g. metformin, procainamide Manufacturer advises avoid concomitant use Possible increased risk of bradycardia when given in combination Possible increased risk of bradycardia when given in combination Manufacturer advises caution Possible increased risk of bradycardia when given in combination Possible increased risk of bradycardia when given in combination Manufacturer advises caution Plasma concentration of crizotinib possibly increased, manufacturer advises avoid combination Possible increased risk of bradycardia when given in combination Crizotinib increases plasma concentration of midazolam Concomitant use may increase substrate concentration. Caution should be used, in particular SPC (14) SPC (14) 8
Crizotinib continued Oestrogens P-glycoprotein substrates Pilocarpine Pimozide Progestrogens Sirolimus St Johns Wort Strong CYP3A4 inhibitors, inducers and substrates CYP2B6 substrates e.g. bupropion, efavirenz Tacrolimus UGT1A1 & UGT2B7 substrates e.g. raltegravir, irinotecan, morphine, naloxone with substrates with a narrow therapeutic window Contraceptive effect of oestrogens possibly reduced when used in combination SPC (14) Concomitant use may increase substrate concentration. Caution should be used, in particular with substrates with a narrow therapeutic window SPC (14) Possible increased risk of bradycardia when given in combination Manufacturer advises caution with combination Contraceptive effect of proestrogens possibly reduced SPC (14) when used in combination Manufacturer advises caution with combination Plasma concentration of Crizotinib possibly reduced Concomitant use may affect Crizotinib and substrate plasma concentrations. Caution should be used, in particular with substrates with a narrow therapeutic window Concomitant use may affect substrate plasma concentrations. Caution should be used, in particular with substrates with a narrow therapeutic window SPC (14) Manufacturer advises caution with combination Concomitant use may affect substrate plasma concentrations. Caution should be used, in particular with substrates with a narrow therapeutic window Cyclophosphamide ACE inhibitors Alcohol May increase risk of leucopenia Combination may increase cyclophosphamide associated nausea and vomiting. Reports of reduced antitumour activity in animal models. SPC (15) 9
Cyclophosphamide Continued Allopurinol Amiodarone Amphoteracin B Aprepitant Azathioprine Azole antifungals Bupropion Busulfan Cardiotoxic drugs Chloral hydrate Chloramphenicol Ciclosporin Cimetidine Ciprofloxacin Cisplatin Potential for increased risk of toxicity and bone marrow suppression when used in combination Concomitant use may lead to early onset pulmonary toxicity Increased risk of nephrotoxicity May delay activation of cyclophosphamide Increase risk of hepatotoxicity and liver necrosis Fluconazole and intraconazole inhibit the metabolism of cyclophosphamide, leading to increased toxicity May delay activation of cyclophosphamide Cyclophosphamide serum levels may be increased (and active metabolite decreased) if given within 24 hours of busulfan Concomitant use requires careful supervision of heart function due to increased cardiotoxic risk when used in combination Increased concentration of cytotoxic metabolites when used in combination May delay activation of cyclophosphamide Combination may result in lower ciclosporin plasma concentration and increase risk of graft versus host disease Increased concentration of cytotoxic metabolites when used in combination May cause regression of underlying disease if administered in combination (for conditioning prior to bone marrow transplant) Increased renal toxicity when used in combination or in patients who have had prior treatment with cisplatin 10 SPC (15) SPC (15)
Cyclophosphamide continued Coumarins Combination may affect INR, monitor CYP3A4 inducers Concentration and efficacy of cyclophosphamide affected when used in combination CYP2B6 & CYP3A4 inhibitors and substrates e.g. Nevirapin, Ritonavir, Bupropion Dabrafenib Depolarising muscle relaxants Digoxin Disulfiram Etanercept GCSF Glyceraldehyde Indomethacin Live vaccines Metronidazole Natalizumab Co-administration may reduce the efficacy of cyclophosphamide or affect substrate metabolism Increased concentration of cytotoxic metabolites when used in combination If cyclophosphamide administered within 10 days of anaesthesia, may result in prolonged apnoea. Manufacturer advises to inform anaesthetist Cyclophosphamide possibly reduces absorption of digoxin tablets Increased concentration of cytotoxic metabolites when used in combination Combination may increase risk of non-cutaenous solid malignancies Increased risk of pulmonary toxicity when used in combination Increased concentration of cytotoxic metabolites when used in combination Case report of acute water intoxication when used in combination Increased risk of infection post vaccination, manufacturer advises avoid Case report of acute encephalopathy in patient receiving this combination. Causality unclear. Increased risk of haematotoxicity/bone marrow SPC (15) 11
Cyclophosphamide Continued Cytarabine Ondansetron Oral antidiabetic drugs particularly Sulfonylurea derivatives Paclitaxel Pentostatin Prasugrel Protease inhibitors Rifampicin suppression Reduced cyclophosphamide AUC when used in combination in high dose regimes Potentiated by cyclophosphamide monitor blood glucose levels Increased risk of haematotoxicity/bone marrow suppression when cyclophosphamide administered after paclitaxel Increased risk of toxicity when pentostatin is given with high dose cyclophosphamide May delay activation of cyclophosphamide Concomitant use may increase the concentration of cytotoxic metabolites Increased metabolism of cyclophosphamide 12 SPC (15) SPC (15) Sulfonamides May delay activation of cyclophosphamide Suxamethonium Combination enhances effect of suxamethonium Tamoxifen May increase risk of thromboembolic complications Thiazide diuretics Increased risk of haematotoxicity/bone marrow suppression Thiotepa strongly inhibits cyclophosphamide bioactivation in high dose regimes when administered 1 Thiotepa hour before SPC (15) Verapamil Impaired intestinal absorption of orally administered verapamil has been reported Zidovudine Increased risk of haematotoxicity/bone marrow suppression Digoxin Cytarabine possibly reduces absorption of digoxin tablets
Cytarabine continued Dacarbazine Dasatinib Flucytosine Aldesleukin Cytochrome P450 (CYP1A1, CYP1A2 and CYP2E1) Methoxypsoralen Boceprevir CYP3A4 inhibitors & inducers H2 antagonists Proton pump inhibitors Cytarabine possibly reduces Flucytosine plasma concentration SPC (16) Avoid concomitant use Dacarbazine is metabolised by cytochrome P450, therefore levels may be altered in co-administered with other substrates SPC (17) Enhanced effect when used in combination due to photosensitisation Avoid concomitant use May affect dasatinib plasma concentrations, avoid concomitant use with strong inducers and inhibitors Long term gastric acid suppression is likely to reduce SPC (18) Dasatinib exposure. Consider use of antacids instead. Long term gastric acid suppression is likely to reduce Dasatinib exposure. Consider use of antacids instead. Daunorubicin Simvastatin Rifampicin Cardiotoxic drugs Hepatotoxic drugs Live vaccines Dasatinib possibly increases plasma concentrations of simvastatin Reduced plasma concentration of Dasatinib avoid concomitant use Concomitant use requires careful supervision of heart function Concomitant use may affect Daunorubicin elimination and consequently increase toxicity Increased risk of infection post vaccination, manufacturer advises avoid SPC (19) 13
Decitabine Docetaxel Doxorubicin Ciclosporin CYP3A4 inducers and inhibitors Lapatinib Ritonavir Sorafenib Amphoteracin B Anticonvulsants Anthracyclines and cardiotoxic medication Calcium channel blockers (verapamil) Ciclosporin Cytarabine CYP3A4 inhibitors CYP450 inducers and inhibitors Digoxin Epirubicin Hepatotoxic medication (e.g. 6- mercaptopurine) Paclitaxel Possible interaction noted Metabolism of docetaxel clearance altered, may lead to increased toxicity or reduced efficacy of docetaxel Increased risk of neutropenia Plasma concentration of docetaxel increased Increased plasma concentration of docetaxel Marked increase in nephrotoxicity Reduced absorption of anticonvulsants when administered in combination with doxorubicin Monitor cardiac function as increased risk of cardiotoxicity Plasma concentration of doxorubicin is increased Increased risk of neurotoxicity Potential for severe infections and necrosis of intestine Reduction in plasma concentration May affect doxorubicin metabolism, leading to increased toxicity or decreased efficacy Possibility of reduced absorption of oral bioavailability of digoxin May increase concentration of epirubicin metabolites when docetaxel administered immediately after epirubicin Increased risk of hepatotoxicity when used in combination Manufacturer advises to leave at least 24 hours 14 SPC (20) SPC (21) SPC (21)
Doxorubicin continued Ritonavir Sorafenib Stavudine Uric acid lowering agents Vaccines between infusing both drugs as elimination of doxorubicin may be reduced if given within 24 hours of paclitaxel Elevated serum doxorubicin concentration Plasma concentration of doxorubicin possibly increased Doxorubicin possibly inhibits effects of Stavudine Doxorubicin therapy may lead to an increase in serum uric acid Doxorubicin patients should not be actively SPC (21) vaccinated and also avoid contact with patients who have recently had polio vaccination Decitabine Epirubicin Cardiotoxic medication Monitor cardiac function as increased risk of cardiotoxicity Ciclosporin Plasma concentration of epirubicin is increased by ciclosporin Cimetidine Increases plasma concentration of epirubicin, not explained by CYP activity Dexverapamil Possible increased bone marrow suppression May increase concentration of epirubicin metabolites Docetaxel when docetaxel administered immediately after epirubicin Interferon alpha 2b May reduce total clearance of epirubicin Hepatotoxic medication May affect epirubicin efficacy and toxicity Live vaccines Live vaccines should be avoided Paclitaxel Increased risk of toxicity, manufacturers advise at least 24 hours between infusions if used in 15 SPC (22) SPC (22)
Epirubicin continued Eribulin Erlotinib combination Quinine Can accelerate distribution of epirubicin into the SPC (22) tissues Antiepileptics e.g. carbamazepine & phenytoin Plasma concentration of eribulin possibly reduced CYP3A4 Enzyme inducers Potential for reduced eribulin plasma concentration Inhibitors of hepatic transport proteins May reduce elimination of eribulin and result in up to SPC (23) three fold increase in plasma concentration Rifampicin Plasma concentration of eribulin possibly reduced St John s Wort Plasma concentration of eribulin possibly reduced Eribulin may inhibit CYP3A4, resulting in increased Substrates of CYP3A4 plasma concentration of the substrate. Avoid concomitant use if substrate has narrow therapeutic SPC (23) range Plasma concentration of erlotinib potentially reduced Antacids by antacids. Give antacids at least 4 hours before or 2 hours after Antivirals (bocepravir) Avoid co-administration Capecitabine Plasma concentration of erlotinib possibly increased by capecitabine Ciprofloxacin Plasma concentration of erlotinib increased by ciprofloxacin Coumarins Enhanced anticoagulant effect, monitor INR regularly as increased risk of bleeding CYP1A2 inhibitors/inducers May alter erlotinib levels SPC (24) CYP3A4 inhibitors/inducers May alter erlotinib levels H2 receptor antagonists Avoid concomitant use with cimetidine, famotidine, 16
Erlotinib continued Estramustine Etoposide nizatidine. Give erlotinib at least 2 hours before or 10 hours after ranitidine Nicotine May reduce plasma concentration smoking cessation advice should be given SPC (24) NSAIDs Increased bleeding risk with used in combination P-glycoprotein inhibitors May alter erlotinib levels SPC (24) Proton pump inhibitors (PPIs) Proteasome inhibitors Rifampicin Statins UGT1A1 substrates ACE inhibitors Antacids Calcium salts May alter erlotinib levels manufacturers recommend avoid concomitant use Concomitant use may affect plasma concentrations due to effect on EGFR degradation Reduced plasma concentration of erlotinib May increase risk of rhabdomyolysis Concomitant use may affect substrate plasma concentrations. Caution should be used, in particular with substrates with a narrow therapeutic window Potential interaction cannot be ruled out, leading to increased risk of angioneurotic oedema Absorption of Estramustine possibly reduced, avoid concomitant use Absorption of Estramustine reduced by calcium salts avoid combination SPC (24) SPC (25) Sodium clodronate Plasma concentration of Estramustine possibly increased Atovaquone Increases plasma concentration of etoposide Antiepileptics Etoposide clearance may be increased by phenytoin and phenobarbital SPC (26) Ciclosporin Increased risk of etoposide toxicity with high dose 17
Etoposide continued Everolimus Fludarabine ciclosporin Cisplatin Reduction in clearance of etoposide SPC (26) Coumarins Enhanced anticoagulant effect, monitor INR CYP3A4 inhibitors CYP3A4 inhibitors may increase side effects and toxicity of etoposide Live vaccines Increased risk of infection post vaccination, manufacturer advises avoid Myelosuppressive drugs Potentiates the effect of etoposide and/or coadministered drug on bone marrow SPC (26) St Johns Wort May induce the metabolism of etoposide and also antagonise the effects ACE inhibitors May increase risk of angioedema SPC (27) Antibacterialse.g clarithromycin, erthryomycin, telithromycin, rifampicin May affect everolimus plasma concentration Antifungals e.g. intraconazole, Plasma concentration of everolimus possibly posaconazole, voriconazole increased, avoid concomitant use CYP3A4 inhibitors and inducers May affect everolimus concentrations Live vaccines Increased risk of infection post vaccination, manufacturer advises avoid SPC (27) Octreotide May affect everolimus levels PgP inhibitors and inducers May affect everolimus concentrations St John s Wort Plasma concentration of everolimus possibly reduced, avoid concomitant use Cytarabine May increase concentration of active metabolite of fludarabine SPC (28) 18
Fludarabine continued Fluorouracil Gefitinib Dipyridamole May reduce the efficacy of fludarabine Pentostatin Increased risk of pulmonary toxicity when these drugs are used in combination, leading to fatalities Allopurinol Manufacturer advises avoid, can affect bioavailability of active drug Cimetidine Significant use of cimetidine (4 weeks or more) can increase fluorouracil levels Coumarins Enhanced anticoagulation effect, monitor INR Erlotinib Capecitabine possibly increases plasma concentration of erlotinib Filgrastim Neutropenia possibly exacerbated when given in combination Affects availability of active drug, works in synergistic Leucovorin manner combination is used in treatment but may increase GI side effects Live vaccines Increased risk of infection post vaccination, manufacturer advises avoid Methotrexate Increase in fluorouracil toxicity Metronidazole Increase in fluorouracil toxicity due to reduced metabolism Phenytoin Increase in fluorouracil toxicity due to reduced metabolism Sorivudine and analogues Potentially fatal combination leads to increased fluoropyrimidine activity Temoporfin Increased skin photosensitivity when topical fluorouracil used in combination Antiepileptics Manufacturer advises avoid concomitant use with phenytoin, phenobarbital and carbamazepine SPC (28) SPC (29) SPC (29) 19
Gefitinib continued Gemcitabine Boceprevir Coumarins CYP2D6 inhibitors CYP2D6 substrates CYP3A4 inducers CYP3A4 inhibitors High dose short acting antacids Itraconazole Ranitidine Rifampicin St Johns Wort Coumarins Yellow fever and other live attenuated vaccines Platinum based chemotherapy Radiotherapy Manufacturer advises avoid concomitant use with phenytoin and carbamazepine Enhanced anticoagulant effect, monitor INR regularly May increase gefitinib plasma levels, monitor for increased toxicity Concomitant administration may alter levels of substrate with narrow therapeutic index May decrease gefitinib plasma levels and therefore SPC (30) efficacy May increase gefitinib plasma levels, monitor for increased toxicity May reduce gefitinib plasma levels and therefore efficacy Plasma concentration of gefitinib increased by itraconazole May reduce gefitinib plasma levels and therefore SPC (30) efficacy Plasma concentration of gefitinib reduced - avoid concomitant use Manufacturer advises avoid concomitant use Enhances anticoagulant effect monitor INR closely Increased risk of systemic disease Carboplatin administered immediately after gemcitabine may cause increased severity of thrombocytopenia Gemcitabine may cause radiosensitisation when given SPC (31) 20
Gemcitabine continued Hydroxycarbamide concurrently with (or within 7 days of) radiotherapy SPC (31) Increased risk of toxicity with hydroxycarbamide Antivirals given with didanosine and stavudine, particularly SPC (32) hepatotoxicity Idarubicin Idelalisib Cardiotoxic medication Ciclosporin Cisplatin Coumarins Live vaccines Radiotherapy CYP2C8 substrates CYP3A4 inducers CYP3A4 inhibitors CYP3A4 substrates Monitor cardiac function as increased risk of cardiotoxicity SPC (33) Increased in idarubicin AUC Increased risk of ototoxicity Combination may affect INR, monitor Increased risk of infection post vaccination, manufacturer advises avoid An additive myelosuppressive effect may occur when radiotherapy is given concomitantly or within 2-3 weeks prior to treatment with idarubicin May affect plasma concentration of substrate, use substrates with a narrow therapeutic window with caution Reduction in idelalisib plasma concentration and therefore efficacy if used in combination with moderate and strong inhibitors Increase in idelalisib plasma concentration, monitor for increased risk of adverse reactions. No initial dose adjustment of idelalisib is considered necessary May affect plasma concentration of substrate, use substrates with a narrow therapeutic window with caution 21 SPC (33) SPC (34)
Idelalisib continued Ifosfamide PgP inhibitors Intestinal PgP substrates e.g. dabigatran Substrates of inducible enzymes (e.g., CYP2C9, CYP2C19, CYP2B6 and UGT) ACE inhibitors Alcohol Allopurinol Amiodarone Aminoglycosides Amphoteracin B Antiemetics Antihistamines Aprepitant Busulfan Carboplatin &Cisplatin Cardiotoxic drugs Increase in idelalisib plasma concentration, monitor for increased risk of adverse reactions. No initial dose adjustment of idelalisib is considered necessary Increased substrate exposure cannot be excluded. Use substrates with a narrow therapeutic window with caution. Reduced plasma concentration (and therefore efficacy) of substrates cannot be excluded. Use substrates with a narrow therapeutic window with caution. May increase risk of leucopenia Combination may increase ifosfamide associated nausea and vomiting. Reports of reduced antitumour activity in animal models. Potential for increased risk of toxicity and bone marrow suppression when used in combination Concomitant use may lead to early onset pulmonary toxicity Increased risk of nephrotoxicity Increased risk of nephrotoxicity Additive CNS effects may occur when used in combination Additive CNS effects may occur when used in combination Report of increased ifosfamide neurotoxicity Increased risk of haemorrhagic cystitis Increased risk of ototoxicity, nephrotoxicity & haematological toxicity when given in combination Concomitant use requires careful supervision of heart SPC (34) SPC (35) 22
Ifosfamide continued Imatinib Coumarins CYP3A4 inducers CYP2B6 & CYP3A4 inhibitors and substrates e.g. Nevirapin, Ritonavir, Bupropion function due to increased cardiotoxic risk when used in combination Combination may affect INR, monitor Concentration and efficacy of ifosfamide affected when used in combination Co-administration may reduce the efficacy of ifosfamide or affect substrate metabolism Increased gastrointestinal toxicity has been reported Docetaxel when ifosfamide was administered before docetaxel infusion. Increased risk of pulmonary toxicity when used in GCSF combination Formation of the active metabolite of irinotecan may Irinotecan be reduced when irinotecan is administered with ifosfamide Increased risk of infection post vaccination, Live vaccines manufacturer advises avoid Additive CNS effects may occur when used in Narcotics combination Increased risk of haematotoxicity/bone marrow Natalizumab suppression Oral antidiabetic drugs particularly Potentiated by ifosphamide monitor blood glucose Sulfonylurea derivatives levels Tamoxifen May increase risk of thromboembolic complications Boceprevir Avoid concomitant use with Imatinib Imatinib possibly increases plasma concentration of Bosutinib bosutinib. Manufacturer recommends avoid combination or consider reduced dose of bosutinib 23 SPC (35)
Imatinib continued Ciclosporin Coumarins CYP2D6 substrates CYP3A4 inducers CYP3A4 inhibitors CYP3A4 substrates Enzyme inducing antiepileptics e.g. carbamazepine, oxcarbamazepine, phenytoin Everolimus Levothyroxine Paracetamol Rifampicin Simvastatin St Johns Wort Imatinib possibly increases plasma concentration of ciclosporin Monitor INR. SPC states patients should be treated with low molecular weight heparin or standard heparin Use caution when co-administering with substrate that has a narrow therapeutic window Reduces Imatinib plasma concentration and therefore efficacy Increases Imatinib plasma concentration, monitor for toxicity Imatinib may alter the plasma concentration of substrates so caution should be used if they have a narrow therapeutic window, such as ciclosporin May reduce plasma concentration of Imatinib, avoid concomitant use Imatinib increases the plasma concentration of everolimus, consider reduced dose Plasma exposure to levothyroxine may be decreased when used in conjunction with Imatinib. Monitor thyroid function tests. Caution should be used if co-administering high dose Imatinib and paracetamol Plasma concentration of Imatinib reduced, avoid concomitant use Plasma concentration of simvastatin increased Plasma concentration of Imatinib reduced, avoid concomitant use 24 SPC (36) SPC (36)
Imatinib continued Irinotecan Lapatinib Tacrolimus Imatinib increases plasma concentration of tacrolimus Antiepileptics Clearance of irinotecan increased by phenytoin and phenobarbital. Sodium valproate may decrease SPC (37) clearance of irinotecan active metabolite Antivirals (Atazanavir) Metabolism of Irinotecan inhibited by Atazanavir, increased risk of toxicity Bevacizumab May possibly reduce tolerated dose of irinotecan and result in increased incidence of side effects SPC (37) CYP3A4 inducers/inhibitors May affect irinotecan levels. Caution is advised by manufacturer. SPC (37) Itraconazole Increased risk of toxicity when given in combination Ketoconazole Increases concentration of irinotecan active metabolite Lapatinib Plasma concentration of irinotecan active metabolite increased by lapatinib Irinotecan has anticholinesterase activity and may prolong neuromuscular blocking effects of SPC (37) Neuromuscular blocking agents suxamethonium, and may also antagonise neuromuscular blockade of non-depolarising drugs e.g. pancuronium, rocuronium Regorafenib Plasma concentration of irinotecan increased when used in combination Sorafenib St Johns Wort Antibacterials e.g. rifabutin, rifampicin, telithromycin Plasma concentration of irinotecan is increased Increases metabolism of irinotecan, reducing plasma levels Manufacturer advises avoid concomitant use SPC (37) 25
Lapatinib continued Antiepileptics Avoid concomitant use with phenytoin and carbamazepine Antifungals Avoid concomitant use with ketoconazole, itraconazole, posaconazole and voriconazole Antivirals Avoid concomitant use with boceprevir, ritonavir and saquinavir BRCP substrates Lapatinib may affect substrate metabolism. Caution should be used with substrates with a narrow SPC (38) therapeutic window CYP2C8 substrates e.g. repaglinide Manufacturer advises avoid concomitant use with substrates that have a narrow therapeutic window CYP3A4 inducers May decrease lapatinib levels and therefore efficacy May increase plasma lapatinib levels. Coadministration SPC (38) CYP3A4 inhibitors with strong inhibitors should be avoided Docetaxel Possible increased risk of neutropenia when given in combination Food Bioavailability of lapatinib may be affected by food SPC (38) Grapefruit juice Manufacturer advises avoid concomitant use Histamine and H2 proton pump inhibitors Co-administration may result in reduced lapatinib absorption Irinotecan May increase levels of active metabolite of irinotecan OATP1B1 substrates Lapatinib may affect substrate metabolism. Caution should be used with substrates with a narrow therapeutic window SPC (38) Paclitaxel Increase in diarrhoea and neutropenia observed due to increased plasma concentration of paclitaxel Pazopanib Lapatinib increased plasma concentration of pazopanib 26
Lapatinib continued Lenalidomide Lomustine P-glycoprotein substrates Pimozide Proton pump inhibitors Repaglinide (Substrate of CYP2C8) St Johns Wort Ciclosporin Clarithromycin Digoxin Erythropoietic agents Hormone replacement therapy Itraconazole Statins Verapamil Antiepileptics Cimetidine Live vaccines Pre treatment of phenobarbital Co-administration may increase plasma concentration of substrate drug. Manufacturer advises caution with SPC (38) substrates that have a narrow therapeutic window. Manufacturer advises to avoid concomitant use Co-administration may result in reduced lapatinib absorption Manufacturer advises to avoid concomitant use Manufacturer advises to avoid concomitant use Plasma concentration of Lenalidomide possibly increased with used in combination Plasma concentration of Lenalidomide possibly increased with used in combination Lenalidomide possibly increases plasma concentration of digoxin Use combination with caution SPC (39) Increased risk of thrombosis, use with caution Plasma concentration of Lenalidomide possibly increased with used in combination Increase in rhabdomyolysis risk when used in SPC (39) combination Plasma concentration of Lenalidomide possibly increased with used in combination Pharmacokinetics of antiepileptic and/or lomustine SPC (40) may be altered May potentiate bone marrow toxicity Increased risk of infection post vaccination, manufacturer advises avoid SPC (40) May lead to increased elimination and reduced 27
Lomustine efficacy of lomustine SPC (40) continued Theophylline May potentiate bone marrow toxicity Cardiac glycosides Combination possibly reduces absorption of digoxin tablets Ciclosporin May increase risk of impaired renal function. Increased risk of nephrotoxicity. Melphalan Live vaccines Manufacturer advises avoid concomitant use SPC (41) Nalidixic acid May lead to haemorrhagic enterocolitis when used in combination with high dose intravenous melphalan Allopurinol Combination leads to enhanced effects and increased toxicity of mercaptopurine. Reduce mercaptopurine to one quarter of usual dose Aminosalicylates Possible increased risk of leucopenia when given in combination Coumarins Combination may reduce INR, monitor closely Plasma concentration of mercaptopurine may be Mercaptopurine Dairy products reduced by dairy products. Give mercaptopurine 1 hour before or 2 hours after dairy products Febuxostat Manufacturer recommends avoid combination Live vaccines Manufacturer advises avoid concomitant use Methotrexate Combination increases mercaptopurine concentration, particularly when high dose methotrexate used. Dose adjustment may be needed SPC (42) Ribavirin Increased risk of severe myelosuppression Sulfamethoxazole (as co-trimoxazole) Increased risk of haematological toxicity Trimethoprim/co-trimoxazole Increased risk of haematological toxicity Methotrexate Acetazolamide Excretion of methotrexate increased by alkalinisation 28
Methotrexate Continued Acitretin Amphotericin B Chloramphenicol Ciclosporin Ciprofloxacin Cisplatin Dexamethasone Digoxin Doxycycline Leflunomide Live vaccines Neomycin Nitrous oxide NSAIDs of urine Increases methotrexate concentration and may increase hepatotoxicity May delay clearance of methotrexate May affect methotrexate transport function of renal tubules, increasing methotrexate concentration and toxicity Increased risk of methotrexate toxicity Ciprofloxacin may increase methotrexate toxicity Increased risk of pulmonary toxicity when given in combination Possible increased risk of hepatotoxicity when high dose methotrexate given with dexamethasone Methotrexate possibly reduces absorption of digoxin tablets Increased risk of methotrexate toxicity Increased risk of toxicity Increased risk of infection post vaccination, manufacturer advises avoid Absorption of methotrexate may be reduced by combination Antifolate effect of methotrexate increased by nitrous oxide. Avoid combination May affect methotrexate transport function of renal tubules, increasing methotrexate concentration and toxicity. However are used in combination in rheumatic disease SPC (43) SPC (43) Oral hypoglycaemics May affect methotrexate transport function of renal SPC (43) 29
Methotrexate continued Mitoxantrone tubules, increasing methotrexate concentration and toxicity Penicillins Increased risk of methotrexate toxicity Phenytoin Antifolate effect of methotrexate increased by phenytoin Probenecid Excretion of methotrexate possibly reduced by methotrexate Proton pump inhibitors Increased risk of methotrexate toxicity Pyrimethamine Antifolate effect of methotrexate increased by pyrimethamine Sulphonamides Increased risk of methotrexate toxicity Tetracyclines Increased risk of methotrexate toxicity Theophylline Theophylline plasma concentration may be increased by methotrexate Sulfamethoxazole (as co-trimoxazole) Increased risk of haematological toxicity Trimethoprim/co-trimoxazole Thiazide diuretics Vitamin preparations including folic acid Antineoplastic agents Cardiotoxic drugs Ciclosporin Live vaccines Increased risk of haematological toxicity May affect methotrexate transport function of renal tubules, increasing methotrexate concentration and toxicity SPC (43) SPC (43) May alter response to methotrexate Combination may lead to increased risk of acute SPC (44) myeloid leukaemia/myelodysplastic syndromes Concomitant use requires careful supervision of heart function due to increased cardiotoxic risk when used in combination Excretion of mitoxantrone reduced by combination Increased risk of infection post vaccination, manufacturer advises avoid SPC (44) 30
Mitoxantrone continued Nilotinib Paclitaxel Radiotherapy Combination may lead to increased risk of acute myeloid leukaemia/myelodysplastic syndromes SPC (44) Antiarrhythmics and drugs that may prolong the QT interval Use combination with caution SPC (45) Boceprevir Manufacturer advises avoid concomitant use Clarithromycin Manufacturer advises avoid concomitant use Nilotinib absorption and elimination may be affected by use of PgP inhibitors and inducers. Plasma CYP3A4 inhibitors/inducers/substrates concentration of substrate may be affected, use caution with substrates with a narrow therapeutic SPC (45) window Food Avoid food for 2 hours before dose and 1 hour after Grapefruit juice Avoid concomitant use Midazolam Nilotinib increases plasma concentration of midazolam PgP inhibitors/inducers Nilotinib absorption and elimination may be affected by use of PgP inhibitors and inducers SPC (45) Rifampicin Plasma concentration of Nilotinib reduced by rifampicin Ritonavir Plasma concentration of Nilotinib possibly increased by ritonavir Telithromycin Manufacturer advises avoid concomitant use Voriconazole Manufacturer advises avoid concomitant use Manufacturer advises giving paclitaxel before cisplatin Cisplatin due to increased myelosuppressive effect if given SPC (46) afterwards Doxorubicin Paclitaxel should be administered 24 hours after SPC (46) 31
Paclitaxel Pazopanib doxorubicin due to reduced elimination of doxorubicin if given in combination SPC (46) Drugs undergoing hepatic metabolism Caution should be used if given in combination Lapatinib Increase in diarrhoea and neutropenia observed due to increased plasma concentration of paclitaxel Protease inhibitors Caution should be used if given in combination SPC (46) Antibacterials e.g. clarithromycin, telithromycin, rifampicin Antifungals e.g. itraconazole, voriconazole Antivirals BCRP inhibitors/inducers/substrates CYP3A4 inducers/inhibitors Plasma concentration of pazopanib possibly increased by clarithyromycin and telithromycin, consider reducing dose. Plasma concentration of pazopanib possibly reduced by rifampicin Plasma concentration of pazopanib may be increased, consider reduced dose of pazopanib Plasma concentration of pazopanib may be increased. Avoid concomitant use with bocepravir. Increased risk of ventricular arrhythmia when used with saquinavir, avoid concomitant use May affect pazopanib metabolism. Concentration of the substrate may be affected, use caution with substrates with a narrow therapeutic window 32 SPC (47) May affect pazopanib metabolism. Concentration of the substrate may be affected, use caution with substrates with a narrow therapeutic window SPC (47) Food Grapefuit juice H2 antagonists Lapatinib Pazopanib should be administered at least 1 hour before or 2 hours after a meal Manufacturer advises avoid concomitant use Manufacturer advises give at least 2 hours before or 10 hours after H2 antagonist Plasma concentration of pazopanib increased by lapatinib
Pazopanib continued Pemetrexed Pentostatin Platinum Concentration of the substrate may be affected, use OATP1B1 substrates caution with substrates with a narrow therapeutic window May affect pazopanib metabolism. Concentration of PgP inhibitors/inducers the substrate may be affected, use caution with substrates with a narrow therapeutic window SPC (47) Statins Combination may lead to increased ALT levels Concentration of the substrate may be affected, use UGT1A1 substrates caution with substrates with a narrow therapeutic window Coumarins INR may be affected, monitor closely Live vaccines Increased risk of infection post vaccination, SPC (48) manufacturer advises avoid Nephrotoxic drugs Renal excretion of pemetrexed possibly reduced Pyrimethamine Antifolate effect of pemetrexed increased by combination Allopurinol Combination may lead to increased risk of skin reaction SPC (49) Increased risk of toxicity when given with high dose Cyclophosphamide cyclophosphamide. Manufacturer advises avoid concomitant use Fludarabine Increased risk of pulmonary toxicity when these drugs are used in combination, leading to fatalities Vidarabine Combination may lead to increased side effects from both drugs SPC (49) Antihypertensives May increase potential for nephrotoxicity SPC (50-52) Aldesleukin Manufacturer advises to avoid concomitant use with 33
Compounds Carboplatin Cisplatin Oxaliplatin Allopurinol (and other drugs which affect serum uric acid levels e.g. colchicine, probenecid or sulfinpyrazone) Aminoglycosides Antiepiletics ( see separate phenytoin entry below) Antihistamines - Phenothiazines and others Bleomycin Capreomycin Ciclosporin Diuretics Docetaxel cisplatin May require dosage adjustment as cisplatin can increase serum uric acid concentration SPC (50-52) Increased risk of ototoxicity and nephrotoxicity when used in combination Concomitant use may result in subtherapeutic levels of antiepileptics May mask development of ototoxicity symptoms Increased risk of pulmonary toxicity when cisplatin given with bleomycin Increased risk of ototoxicity and nephrotoxicity when used in combination Risk of excessive immunosuppression and lymphoproliferation Increased risk of nephrotoxicity and ototoxicity when given in combination Increased risk of neurotoxicity when given with cisplatin 34 SPC (50-52) SPC (50-52) SPC (50-52) Ifosphamide Increased risk of ototoxicity when given with cisplatin Lithium Monitoring of lithium levels recommended when a combination of lithium and cisplatin are used SPC (50-52) Live vaccines Manufacturer advises to avoid concomitant use Methotrexate Increased risk of pulmonary toxicity when cisplatin given with methotrexate Nephrotoxic drugs May increase risk of toxicity due to changes in renal clearance SPC (50-52) Oral anticoagulants May affect the INR, monitor closely
Platinum Compounds Carboplatin Cisplatin Oxaliplatin Pomalidomide Ponatinib Ototoxic drugs Paclitaxel Penicillamine and other chelating agents Phenytoin Polymixin Pyridoxine Radiation Topotecan Vancomycin Vinblastine CYP1A2 inhibitors Coumarins Fluvoxamine BRCP substrates May increase risk of toxicity due to changes in renal clearance May reduce clearance of cisplatin when cisplatin treatment given prior to paclitaxel, increasing neurotoxicity May reduce efficacy of platinum compounds Platinum possibly reduces plasma concentration of phenytoin Increased risk of ototoxicity and nephrotoxicity when used in combination May increase time to response when used in combination Increased risk of myelosuppression If either cisplatin or carboplatin is given on day 1 of the topotecan dosing, a lower dose of each agent SPC (50-52) must be given to improve tolerability compared to the dose of each agent which can be given if the platinum agent is given on day 5 of the topotecan dosing Increased risk of nephrotoxicity and possibly ototoxicity with cisplatin May lead to Raynaud-phenomenon when given with SPC (50-52) cisplatin Patients should be closely monitored for the occurrence of adverse reactions SPC (53) Close monitoring of INR is recommended Plasma concentration of Pomalidomide increased by combination Plasma concentration of substrate may be affected. SPC (54) Caution should be used with substrates with a narrow 35
Ponatinib Continued Procarbazine Raltitrexed Ruxolitinib therapeutic window CYP3A4 inhibitors & inducers May affect ponatinib plasma concentration. Consider dose adjustment. Grapefuit juice Manufacturer advises avoid concomitant use Plasma concentration of substrate may be affected. SPC (54) PgP substrates Caution should be used with substrates with a narrow therapeutic window Alcohol Risk of disulfiram like reaction Anticholinergic drugs Effects of anticholinergics may be potentiated SPC (55) Antiepileptics e.g. carbamazepine, Increased risk of hypersensitivity reactions when phenobarbital, phenytoin given in combination Antihypertensives Effect of antihypertensives may be potentiated Barbituates Effects of barbituates may be potentiated Central nervous system depressants Effects of CNS depressants may be potentiated SPC (55) Digoxin Procarbazine possibly reduces absorption of digoxin tablets Food Procarbazpine is a weak MAO inhibitor, use in combination with certain foods with caution SPC (55) Narcotic analgesics particularly pethidine Effects of narcotic analgesics may be potentiated Folates Manufacturer advises avoid concomitant use Antibacterials e.g. clarithromycin, telithromycin, rifampicin Antifungals e.g. fluconazole, itraconazole, posaconazole, voriconazole Plasma concentration of ruxolitinib possibly increased by clarithyromycin and telithromycin, consider reducing dose. Plasma concentration of ruxolitinib possibly reduced by rifampicin Plasma concentration of ruxolitinib may be increased, consider reduced dose of ruxolitinib SPC (56) 36
Ruxolitinib continued Sorafenib Antivirals e.g. boceprevir, indinavir, lopinavir, ritonavir, saquinavir & telaprevir Plasma concentration of ruxolitinib may be increased. Consider reduced dose of ruxolitinib Plasma concentration of substrate may be affected. BRCP substrates Caution should be used with substrates with a narrow therapeutic window SPC (56) CYP2C9 inhibitors & inducers May affect plasma concentration of ruxolitinib, consider adjusting dose and increasing monitoring CYP3A4 inhibitors & inducers May affect plasma concentration of ruxolitinib, consider adjusting dose and increasing monitoring Plasma concentration of substrate may be affected. PgP substrates Caution should be used with substrates with a narrow therapeutic window Boceprevir Avoid concomitant use Capecitabine Concomitant use resulted in small to moderate increases in capecitabine plasma concentration SPC (57) Coumarins Possible increased INR, monitor closely CYP3A4 inducers May affect sorafenib plasma concentration SPC (57) Docetaxel Doxorubicin Irinotecan Neomycin PgP substrates Combination may lead to increased plasma concentration of docetaxel Combination possibly leads to increased plasma concentration of doxorubicin Combination possibly leads to increased plasma concentration of irinotecan Bioavailability of sorafenib reduced by neomycin Plasma concentration of substrate may be affected. Caution should be used with substrates with a narrow therapeutic window SPC (57) 37
Sorafenib continued Sunitinib Temsirolimus Rifampicin Boceprevir CYP3A4 inducers CYP3A4 inhibitors Rifampicin Temsirolimus ACE inhibitors Plasma concentration of sorafenib reduced by rifampicin Avoid concomitant use May decrease sunitinib plasma concentration, consider adjusting dose SPC (58) May increase sunitinib plasma concentration, consider adjusting dose Plasma concentration of sunitinib reduced by rifampicin Combination leads to dose limiting toxicity e.g. grade 3 & 4 erythematous maculopapular rash, SPC (58) gout/cellulitis requiring hospitalisation Increased risk of angioneurotic oedema-type reactions, including delayed reactions occurring 2 months after initiation of therapy SPC (59) Amphiphilic agents e.g. amiodarone, Combination may result in increased risk of statins pulmonary toxicity CYP3A4 inhibitors, inducers & substrates. Itraconazole PgP substrates Rifampicin May affect temsirolimus plasma concentration. Plasma concentration of substrate may be affected. Caution should be used with substrates with a narrow therapeutic window Plasma concentration of Temsirolimus possibly increased, avoid concomitant use Plasma concentration of substrate may be affected. Caution should be used with substrates with a narrow therapeutic window Plasma concentration of active metabolite of SPC (59) 38