chapter
Cytotoxics
Pages 57

Watch for poor response to digoxin; check levels if signs of ↓ effect and consider swapping to liquid digoxin or liquid-containing capsules

ALL VACCINES – LIVE Risk of contracting disease from the vaccine

↓ immunity Avoid live vaccines for at least 6 months after completing chemotherapy

Effect Mechanism Precautions

ARSENIC TRIOXIDE 1. ANTIARRHYTHMICS – amiodarone, disopyramide, procainamide, propafenone 2. ANTIBIOTICS – macrolides (especially azithromycin, clarithromycin, parenteral erythromycin, telithromycin), quinolones (especially moxifloxacin), quinupristin/dalfopristin 3. ANTIDEPRESSANTS – TCAs, venlafaxine 4. ANTIEMETICS – dolasetron 5. ANTIFUNGALS – fluconazole, posaconazole, voriconazole 6. ANTIHISTAMINES – terfenadine, hydroxyzine, mizolastine 7. ANTIMALARIALS – artemether with lumefantrine, chloroquine, hydroxychloroquine, mefloquine, quinine 8. ANTIPROTOZOALS – pentamidine isetionate 9. ANTIPSYCHOTICS – atypicals, phenothiazines, pimozide 10. BETA-BLOCKERS – sotalol 11. BRONCHODILATORS – parenteral bronchodilators 12. CNS STIMULANTS – atomoxetine

Risk of ventricular arrhythmias, particularly torsades de pointes

Additive effect; these drugs cause prolongation of the Q-T interval

Avoid co-administration

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ANTICANCER AND IMMUNOMODULATING DRUGS CYTOTOXICS Busulfan

≠ Possibly via inhibition of intestinal CYP3A4

Clinical significance unknown. Monitor more closely

BEXAROTENE LIPID-LOWERING DRUGS – GEMFIBROZIL

Gemfibrozil may ≠ bexarotene levels

Uncertain at present Avoid co-administration

BLEOMYCIN BLEOMYCIN ANTICANCER AND

IMMUNOMODULATING DRUGS – CISPLATIN

≠ bleomycin levels, with risk of pulmonary toxicity

Elimination of bleomycin is delayed by cisplatin due to ↓ glomerular filtration. This is most likely with accumulated doses of cisplatin in excess of 300 mg/m2

Monitor renal function and adjust dose of bleomycin as per creatinine clearance. Monitor clinically, radiologically and with lung function tests for pulmonary toxicity

BORTEZOMIB

BORTEZOMIB ANTIDIABETIC DRUGS – CHLORPROPAMIDE

Likely to ≠ hypoglycaemic effect of chlorpropamide

Unknown Watch for and warn patients about symptoms of hypoglycaemia ➣ For signs and symptoms of hypoglycaemia, see Clinical Features of Some Adverse Drug Interactions, Hypoglycaemia

BUSULFAN

BUSULFAN ANALGESICS – PARACETAMOL Busulfan levels may be ≠ by co-administration of paracetamol

Uncertain; paracetamol probably inhibits metabolism of busulfan

Manufacturers recommend that paracetamol should be avoided for 3 days before administering parenteral busulfan

BUSULFAN ANTIBIOTICS

BUSULFAN MACROLIDES – CLARITHROMYCIN, ERYTHROMYCIN, TELITHROMYCIN

≠ plasma concentrations of busulfan and ≠ risk of toxicity of busulfan such as veno-occlusive disease and pulmonary fibrosis

Busulfan clearance may be ↓ by 25%, and the AUC of busulfan may ≠ by 1500mol/L

Monitor clinically for veno-occlusive disease and pulmonary toxicity in transplant patients. Monitor busulfan blood levels as AUC below 1500mol/L per minute tends to prevent toxicity

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Mechanism Precautions Uncertain Watch for early features of toxicity

BUSULFAN CYCLOPHOSPHAMIDE ≠ incidence of veno-occlusive disease and mucositis when cyclophosphamide is given 24 hours after the last dose of busulfan. Possibly also ↓ effect of cyclophosphamide

There is ↓ clearance and ≠ elimination half-life of cyclophosphamide, and ≠ concentrations of the active metabolite 4-hydroxycyclophosphamide

Administer cyclophosphamide at least 24 hours after the last dose of busulfan

BUSULFAN TIOGUANINE ≠ risk of nodular regenerative hyperplasia of the liver, oesophageal varices and portal hypertension

Mechanism uncertain Monitor liver function and for clinical and biochemical indices of liver toxicity (e.g. ascites, splenomegaly). Ask patients to report any symptoms suggestive of oesophageal bleeding

BUSULFAN ANTIEPILEPTICS – FOSPHENYTOIN, PHENYTOIN

↓ plasma concentrations of busulfan (by approximately 15%)

Due to induction of glutathione S-transferase by fosphenytoin

Be aware. Clinical significance may be minimal

BUSULFAN ANTIFUNGALS – ITRACONAZOLE

≠ busulfan levels, with risk of toxicity of busulfan, e.g. venoocclusive disease and pulmonary fibrosis

Itraconazole is a potent inhibitor of CYP3A4. Busulfan clearance may be ↓ by 25%, and the AUC of busulfan may ≠ by 1500mol/L

Monitor clinically for veno-occlusive disease and pulmonary toxicity in transplant patients. Monitor busulfan blood levels as AUC below 1500mol/L per minute tends to prevent toxicity

BUSULFAN CALCIUM CHANNEL BLOCKERS

≠ busulfan levels, with risk of toxicity of busulfan, e.g. venoocclusive disease and pulmonary fibrosis, when co-administered with diltiazem, nifedipine or verapamil

Due to inhibition of CYP3A4mediated metabolism of busulfan by these calcium channel blockers. Busulfan clearance may be ↓ by 25%, and the AUC of busulfan may ≠ by 1500mol/L

Monitor clinically for veno-occlusive disease and pulmonary toxicity in transplant patients. Monitor busulfan blood levels as AUC below 1500mol/L per minute tends to prevent toxicity

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ANTICANCER AND IMMUNOMODULATING DRUGS CYTOTOXICS Chlorambucil

Additive toxicity Monitor more closely; monitor FBC regularly

Capecitabine is metabolized to fluorouracil ➣ Flurorouracil/capecitabine, below

CARBOPLATIN ➣ Platinum compounds, below

CARMUSTINE

CARMUSTINE ANTICANCER AND IMMUNOMODULATING DRUGS – ETOPOSIDE (HIGH DOSE)

≠ risk of liver toxicity, which usually occurs after 1-2 months after initiating treatment without an improvement in tumour response

Possible additive hepatotoxic effects

Avoid co-administration

CARMUSTINE ANTIEPILEPTICS - PHENOBARBITAL

↓ plasma concentrations of carmustine and ↓ anti-tumour effect in animal experiments

Attributed to induction of liver metabolizing enzymes of carmustine by phenobarbitone, particularly with long-term therapy

Avoid concurrent use. As this study did not show any interaction with phenytoin, phenytoin may be a suitable alternative antiepileptic

CARMUSTINE H2 RECEPTOR BLOCKERS – CIMETIDINE

≠ adverse effects of alkylating agent, e.g. myelosuppression

Additive toxicity Monitor more closely; monitor FBC regularly

CHLORAMBUCIL

CHLORAMBUCIL AZATHIOPRINE ≠ risk of myelosuppression and immunosuppression. Deaths have occurred following profound myelosuppression and severe sepsis

Additive myelotoxic effects Azathioprine is metabolized to 6-mercatopurine in vivo, which results in additive myelosuppression, immunosuppression and hepatotoxicity

Avoid co-administration

CHLORAMBUCIL H2 RECEPTOR BLOCKERS – CIMETIDINE

≠ adverse effects of alkylating agent, e.g. myelosuppression

Additive toxicity Monitor more closely; monitor FBC regularly

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Mechanism Precautions

CRISANTASPASE ANTICANCER AND IMMUNOMODULATING DRUGS

CRISANTASPASE METHOTREXATE Administration prior to or concurrently may ↓ efficacy of methotrexate

Crisantaspase inhibits protein synthesis and prevents cell entry to S phase, which leads to ↓ efficacy of methotrexate

Administer crisantaspase shortly after methotrexate or 9-10 days before methotrexate

CRISANTASPASE VINCRISTINE ≠ risk of neurotoxicity if concurrently administered or if crisantaspase is administered prior to vincristine

Uncertain but has been attributed by some to effects of crisantaspase on the metabolism of vincristine

Administer vincristine prior to crisantaspase

CYCLOPHOSPHAMIDE

CYCLOPHOSPHAMIDE ANTICANCER AND IMMUNOMODULATING DRUGS

CYCLOPHOSPHAMIDE AZATHIOPRINE ≠ risk of myelosuppression and immunosuppression. Deaths have occurred following profound myelosuppression and severe sepsis

Additive myelotoxic effects. Azathioprine is metabolized to 6-mercatopurine in vivo, which results in additive myelosuppression, immunosuppression and hepatotoxicity

Avoid co-administration

CYCLOPHOSPHAMIDE BUSULFAN ≠ incidence of veno-occlusive disease and mucositis when cyclophosphamide is given 24 hours after the last dose of busulfan. Possibly also ↓ effect of cyclophosphamide

There is ↓ clearance and ≠ elimination half-life of cyclophosphamide, and ≠ concentrations of the active metabolite 4-hydroxycyclophosphamide

Administer cyclophosphamide at least 24 hours after the last dose of busulfan

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ANTICANCER AND IMMUNOMODULATING DRUGS CYTOTOXICS Cyclophosphamide

24 or 72 hours prior to cyclophosphamide

Mechanism is uncertain Administer cyclophosphamide first and then follow with paclitaxel

CYCLOPHOSPHAMIDE PENTOSTATIN ≠ risk of potentially fatal cardiac toxicity

Attributed to interference of adenosine metabolism by cyclophosphamide

Avoid co-administration

CYCLOPHOSPHAMIDE TRASTUZUMAB ≠ risk of cardiac toxicity Possibly additive cardiac toxic effect

Closely monitor cardiac function – clinically and electrocardiographically

CYCLOPHOSPHAMIDE ANTICOAGULANTS – ORAL Episodes of ≠ anticoagulant effect Not understood but likely to be multifactorial

Monitor INR at least weekly until stable during administration of chemotherapy

CYCLOPHOSPHAMIDE ANTIDIABETIC DRUGS – GLIPIZIDE

Blood sugar levels may be ≠ or ↓ Uncertain Need to monitor blood glucose in patients with concomitant treatment at the beginning of treatment and after 1-2 weeks

CYCLOPHOSPHAMIDE ANTIGOUT DRUGS – ALLOPURINOL

≠ risk of bone marrow suppression Uncertain but allopurinol seems to ≠ cyclophosphamide levels

Monitor FBC closely

CYCLOPHOSPHAMIDE CNS STIMULANTS – MODAFINIL

May cause moderate ≠ in plasma concentrations of cyclophosphamide

Modafinil is a reversible inhibitor of CYP2C19 when used in therapeutic doses

Be aware

CYCLOPHOSPHAMIDE H2 RECEPTOR BLOCKERS – CIMETIDINE

≠ adverse effects of alkylating agent, e.g. myelosuppression

1. Additive toxicity 2. Possible minor inhibition of cyclophosphamide metabolism via CYP2C9

Avoid co-administration of cimetidine with cyclophosphamide

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Mechanism Precautions

CYTARABINE AZATHIOPRINE ≠ risk of myelosuppression and immunosuppression. Deaths have occurred following profound myelosuppression and severe sepsis

Additive myelotoxic effects. Azathioprine is metabolized to 6-mercatopurine in vivo, which results in additive myelosuppression, immunosuppression and hepatotoxicity

Avoid co-administration

CYTARABINE FLUDARABINE ≠ efficacy of cytarabine Uncertain Watch for early features of toxicity of cytarabine

CYTARABINE ANTIFUNGALS – FLUCYTOSINE

↓ flucytosine levels Uncertain Watch for poor response to flucytosine

DACARBAZINE

DACARBAZINE IL-2 ↓ efficacy of dacarbazine ↓ AUC of dacarbazine due to ↓ volume of distribution

The clinical significance is uncertain as both drugs are used in the treatment of melanoma. It may be necessary to monitor clinically and by other appropriate measures of clinical response

DACTINOMYCIN (ACTINOMYCIN D)

DACTINOMYCIN AZATHIOPRINE ≠ risk of myelosuppression and immunosuppression. Deaths have occurred following profound myelosuppression and severe sepsis

Additive myelotoxic effects. Azathioprine is metabolized to 6-mercatopurine in vivo, which results in additive myelosuppression, immunosuppression and hepatotoxicity

Avoid co-administration

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ANTICANCER AND IMMUNOMODULATING DRUGS CYTOTOXICS Docetaxel

Rifampicin ≠ metabolism of dasatinib

Avoid co-administration

DASATINIB H2 RECEPTOR BLOCKERS – FAMOTIDINE

Possible ↓ dasatinib levels Famotidine ≠ metabolism of dasatinib

Consider using alternative acidsuppression therapy

DASATINIB LIPID-LOWERING DRUGS – SIMVASTATIN

Possible ↓ simvastatin levels ≠ metabolism of simvastatin Monitor lipid profile closely and adjust simvastatin dose accordingly when starting and stopping co-administration

DAUNORUBICIN

DAUNORUBICIN ANTICANCER AND IMMUNOMODULATING DRUGS

DAUNORUBICIN AZATHIOPRINE ≠ risk of myelosuppression and immunosuppression. Deaths have occurred following profound myelosuppression and severe sepsis

Additive myelotoxic effects. Azathioprine is metabolized to 6-mercatopurine in vivo, which results in additive myelosuppression, immunosuppression and hepatotoxicity

Avoid co-administration

DAUNORUBICIN TRASTUZUMAB ≠ risk of cardiac toxicity Possibly additive cardiac toxic effect

Closely monitor cardiac function – clinically and electrocardiographically.