ABSTRACT
Avoid co-administration
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DRUGS TO TREAT INFECTIONS ANTIMALARIALS Artemether with lumefantrine
Additive effect Avoid co-administration
LUMEFANTRINE
ARTEMETHER WITH LUMEFANTRINE
REBOXETINE, SNRIs, TRYPTOPHAN
≠ artemether/lumefantrine levels, with risk of toxicity, including arrhythmias
Uncertain Avoid co-administration
ARTEMETHER WITH LUMEFANTRINE
ST JOHN’S WORT This antimalarial may cause doserelated dangerous arrhythmias
A substrate mainly of CYP3A4, which may be inhibited by St John’s wort
Manufacturers recommend avoidance of antidepressants
ARTEMETHER WITH LUMEFANTRINE
SSRIs This antimalarial may cause doserelated dangerous arrhythmias
A substrate mainly of CYP3A4, which may be inhibited by high doses of fluvoxamine and to a lesser degree by fluoxetine
Manufacturers recommend avoidance of antidepressants
ARTEMETHER WITH LUMEFANTRINE
ANTIMALARIALS Risk of arrhythmias Additive effect Avoid co-administration
ARTEMETHER WITH LUMEFANTRINE
ANTIVIRALS – PROTEASE INHIBITORS
≠ artemether levels Uncertain; possibly inhibited metabolism
Avoid co-administration
ARTEMETHER WITH LUMEFANTRINE
BETA-BLOCKERS – METOPROLOL
≠ risk of toxicity Uncertain Avoid co-administration
ARTEMETHER WITH LUMEFANTRINE
GRAPEFRUIT JUICE Possibly ≠ efficacy and adverse effects
≠ bioavailability; ↓ presystemic metabolism. Constituents of grapefruit juice irreversibly inhibit intestinal cytochrome CYP3A4
Monitor more closely. No ECG changes were seen in the study
ARTEMETHER WITH LUMEFANTRINE
H2 RECEPTOR BLOCKERS – CIMETIDINE
≠ efficacy and adverse effects of antimalarials
Inhibition of metabolism, some definitely via CYP3A4
Avoid co-administration
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Mechanism Precautions
ATOVAQUONE RIFAMPICINS Both rifampicin and rifabutin ↓ atovaquone levels, although the effect is greater with rifampicin (↓ AUC by 50% cf. 34% for rifabutin)
Uncertain because atovaquone is predominantly excreted unchanged via the gastrointestinal route
Avoid co-administration with rifampicin. Take care with rifabutin and watch for poor response to atovaquone
ATOVAQUONE TETRACYCLINE ↓ atovaquone levels (40%) Uncertain Not clinically significant; combination therapy has been used effectively
ATOVAQUONE ANTIEMETICS – METOCLOPRAMIDE ↓ atovaquone levels Uncertain Avoid; consider an alternative antiemetic
ATOVAQUONE ANTIVIRALS – ZIDOVUDINE Atovaquone ≠ zidovudine levels
Atovaquone inhibits the glucuronidation of zidovudine
Uncertain clinical significance. Monitor FBC, LFTs and lactate closely during co-administration
ATOVAQUONE H2 RECEPTOR BLOCKERS – CIMETIDINE ≠ efficacy and adverse effects of antimalarials
Inhibition of metabolism, some definitely via CYP3A4
Avoid co-administration
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DRUGS TO TREAT INFECTIONS ANTIMALARIALS Chloroquine/hydroxychloroquine
CHLOROQUINE/ HYDROXYCHLOROQUINE
1. ANTIARRHYTHMICS – amiodarone, disopyramide, procainamide, propafenone 2. ANTIBIOTICS – macrolides (especially azithromycin, clarithromycin, parenteral erythromycin, telithromycin), quinolones (especially moxifloxacin), quinupristin/ dalfopristin 3. ANTICANCER AND IMMUNOMODULATING DRUGS – arsenic trioxide 4. ANTIDEPRESSANTS – TCAs, venlafaxine 5. ANTIEMETICS – dolasetron 6. ANTIFUNGALS – fluconazole, posaconazole, voriconazole 7. ANTIHISTAMINES – terfenadine, hydroxyzine, mizolastine 8. ANTIMALARIALS – artemether with lumefantrine, mefloquine, quinine 9. ANTIPROTOZOALS – pentamidine isetionate 10. ANTIPSYCHOTICS – atypicals, phenothiazines, pimozide 11. BETA-BLOCKERS – sotalol 12. BRONCHODILATORS – parenteral bronchodilators 13. 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
CHLOROQUINE AGALSIDASE BETA ↓ efficacy of agalsidase beta
Inhibition of intracellular activity of agalsidase beta
Avoid co-administration – manufacturers’ recommendation
CHLOROQUINE ANTACIDS ↓ chloroquine levels ↓ absorption Separate doses by at least 4 hours
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Mechanism Precautions
ciclosporin
Likely inhibition of ciclosporin Monitor renal function weekly
HYDROXYCHLOROQUINE PORFIMER ≠ risk of photosensitivity reactions Attributed to additive effects Avoid exposure of skin and eyes to direct sunlight for 30 days after porfimer therapy
CHLOROQUINE ANTIDIARRHOEAL DRUGS – KAOLIN
↓ chloroquine levels ↓ absorption Separate doses by at least 4 hours
CHLOROQUINE ANTIEPILEPTICS Risk of seizures Chloroquine can ↓ seizure threshold
Care with co-administration; ≠ dose of antiepileptic if ≠ incidence of fits
CHLOROQUINE ANTIMALARIALS – MEFLOQUINE
Risk of seizures Additive effect Warn patient of the risk; patients should be advised to avoid driving while taking these drugs in combination
CHLOROQUINE CARDIAC GLYCOSIDES – DIGOXIN
Chloroquine may ≠ plasma concentrations of digoxin
Uncertain at present Monitor digoxin levels; watch for digoxin toxicity
CHLOROQUINE DRUG DEPENDENCE THERAPIES – BUPROPION
≠ risk of seizures. This risk is marked in elderly people, in patients with a history of seizures, with addiction to opiates/cocaine/ stimulants, and in diabetics treated with oral hypoglycaemics or insulin
Bupropion is associated with a dose-related risk of seizures. These drugs, which lower seizure threshold, are individually epileptogenic. Additive effects occur when they are combined
Extreme caution. The dose of bupropion should not exceed 450 mg/day (or 150 mg/day in patients with severe hepatic cirrhosis)
CHLOROQUINE H2 RECEPTOR BLOCKERS – CIMETIDINE
≠ efficacy and adverse effects of chloroquine
Inhibition of metabolism and excretion
Consider ranitidine as an alternative or take cimetidine at least 2 hours after chloroquine
CHLOROQUINE LARONIDASE ↓ efficacy of laronidase Uncertain Avoid co-administration
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DRUGS TO TREAT INFECTIONS ANTIMALARIALS Mefloquine
↓
These antimalarials occasionally cause muscle weakness, which may exacerbate the symptoms of myasthenia gravis
Watch for poor response to these parasympathomimetics and ≠ dose accordingly
MEFLOQUINE
MEFLOQUINE DRUGS THAT PROLONG THE Q-T INTERVAL
MEFLOQUINE 1. ANTIARRHYTHMICS – amiodarone, disopyramide, procainamide, propafenone 2. ANTIBIOTICS – macrolides (especially azithromycin, clarithromycin, parenteral erythromycin, telithromycin), quinolones (especially moxifloxacin), quinupristin/ dalfopristin 3. ANTICANCER AND IMMUNOMODULATING DRUGS – arsenic trioxide 4. ANTIDEPRESSANTS – TCAs, venlafaxine 5. ANTIEMETICS – dolasetron 6. ANTIFUNGALS – fluconazole, posaconazole, voriconazole 7. ANTIHISTAMINES – terfenadine, hydroxyzine, mizolastine 8. ANTIMALARIALS – artemether with lumefantrine, chloroquine, hydroxychloroquine, quinine 9. ANTIPROTOZOALS – pentamidine isetionate 10. ANTIPSYCHOTICS – atypicals, phenothiazines, pimozide 11. BETA-BLOCKERS – sotalol 12. BRONCHODILATORS – parenteral bronchodilators 13. 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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Mechanism Precautions Mefloquine can ↓ seizure
threshold Care with co-administration; ≠ dose of antiepileptic if ≠ incidence of fits
MEFLOQUINE ANTIMALARIALS – CHLOROQUINE, QUININE
Risk of seizures Additive effect Warn patients of the risk; patients should be advised to avoid driving while taking these drugs in combination
MEFLOQUINE BETA-BLOCKERS ≠ risk of bradycardia Mefloquine can cause cardiac conduction disorders, e.g. bradycardia. Additive bradycardic effect. Single case report of cardiac arrest with co-administration of mefloquine and propanolol possibly caused by Q-T prolongation
Monitor PR closely
MEFLOQUINE CALCIUM CHANNEL BLOCKERS
Risk of bradycardia Additive bradycardic effect; mefloquine can cause cardiac conduction disorders, e.g. bradycardia. There is also a theoretical risk of Q-T prolongation with co-administration of mefloquine and calcium channel blockers
Monitor PR closely
MEFLOQUINE CARDIAC GLYCOSIDES – DIGOXIN
Risk of bradycardia Uncertain; probably additive effect; mefloquine can cause AV block
Monitor PR and ECG closely
MEFLOQUINE DRUG DEPENDENCE THERAPIES – BUPROPION
≠ risk of seizures. This risk marked in elderly people, in patients with history of seizures, with addiction to opiates/cocaine/stimulants, and in diabetics treated with oral hypoglycaemics or insulin
Bupropion is associated with a dose-related risk of seizures. These drugs, which lower seizure threshold, are individually epileptogenic. Additive effects occur when they are combined
Extreme caution. The dose of bupropion should not exceed 450 mg/day (or 150 mg/day in patients with severe hepatic cirrhosis)
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DRUGS TO TREAT INFECTIONS ANTIMALARIALS Proguanil
Inhibition of metabolism, some definitely via CYP3A4
Avoid co-administration
mefloquine
Additive effect Monitor ECG closely
PRIMAQUINE
PRIMAQUINE ANTIMALARIALS – ARTEMETHER WITH LUMEFANTRINE
Risk of arrhythmias Additive effect Avoid co-administration
PRIMAQUINE H2 RECEPTOR BLOCKERS – CIMETIDINE
≠ efficacy and adverse effects of antimalarials
Inhibition of metabolism, some definitely via CYP3A4
Avoid co-administration
PRIMAQUINE MEPACRINE ≠ primaquine levels Inhibition of metabolism Warn patients to report the early features of primaquine toxicity (e.g. gastrointestinal disturbance). Monitor FBC closely
PROGUANIL
PROGUANIL ANTACIDS ↓ proguanil levels ↓ absorption Separate doses by at least 4 hours PROGUANIL ANTIDEPRESSANTS – TCAs Possible ≠ plasma concentrations
of proguanil Inhibition of CYP2C19-mediated metabolism of proguanil. The clinical significance of this depends upon whether proguanil’s alternative pathways of metabolism are also inhibited by co-administered drugs
Warn patient to report any evidence of excessive side-effects such as a change in bowel habit or stomatitis
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Mechanism Precautions
LUMEFANTRINE
Additive effect Avoid co-administration
PROGUANIL PYRIMETHAMINE ≠ antifolate effect Additive effect Monitor FBC closely; the effect may take a number of weeks to occur
PROGUANIL CNS STIMULANTS – MODAFINIL
May cause moderate ≠ plasma concentrations of these substrates
Modafinil is a reversible inhibitor of CYP2C19 when used in therapeutic doses
Be aware
PROGUANIL H2 RECEPTOR BLOCKERS – CIMETIDINE
↓ efficacy of proguanil ↓ absorption and ↓ formation of active metabolite
Avoid concomitant use. Clinical significance is not established; effectiveness of malarial prophylaxis may be ↓
PYRIMETHAMINE
PYRIMETHAMINE ANTIBIOTICS – SULPHONAMIDES, TRIMETHOPRIM
≠ antifolate effect Additive effect Monitor FBC closely; the effect may take a number of weeks to occur
PYRIMETHAMINE ANTIEPILEPTICS – PHENYTOIN
1. ↓ efficacy of phenytoin 2. ≠ antifolate effect
1. Uncertain 2. Additive effect 1. Care with co-administration; ≠ dose of antiepileptic if ≠ incidence of fits 2. Monitor FBC closely; the effect may take a number of weeks to occur
PYRIMETHAMINE ANTIMALARIALS
PYRIMETHAMINE ARTEMETHER WITH LUMEFANTRINE
Risk of arrhythmias Additive effect Avoid co-administration
PYRIMETHAMINE PROGUANIL ≠ antifolate effect Additive effect Monitor FBC closely; the effect may take a number of weeks to occur
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DRUGS TO TREAT INFECTIONS ANTIMALARIALS Pyrimethamine
Pyrimethamine should not be used alone and is combined with sulfadoxine. Pyrimethamine and methotrexate synergistically induce folate deficiency
Although the toxic effects of methotrexate are more frequent with high doses of methotrexate, it is necessary to do FBC, liver and renal function tests before starting treatment even with low doses, repeating these tests weekly until therapy is stabilized and thereafter every 2-3 months. Patients should be advised to report symptoms such as sore throat and fever immediately, and also any gastrointestinal discomfort. A profound drop in white cell or platelet counts warrants immediate stoppage of methotrexate therapy and initiation of supportive therapy
PYRIMETHAMINE ANTIVIRALS – ZIDOVUDINE Possibly ≠ adverse effects with zidovudine
Additive toxicity Monitor FBC and renal function closely. ↓ doses as necessary. Use of pyrimethamine as prophylaxis seems to be tolerated
PYRIMETHAMINE H2 RECEPTOR BLOCKERS – CIMETIDINE
≠ efficacy and adverse effects of antimalarials
Inhibition of metabolism, some definitely via CYP3A4
Avoid co-administration
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QUININE 1. ANTIARRHYTHMICS – amiodarone, disopyramide, procainamide, propafenone 2. ANTIBIOTICS – macrolides (especially azithromycin, clarithromycin, parenteral erythromycin, telithromycin), quinolones (especially moxifloxacin), quinupristin/ dalfopristin 3. ANTICANCER AND IMMUNOMODULATING DRUGS – arsenic trioxide 4. ANTIDEPRESSANTS – TCAs, venlafaxine 5. ANTIEMETICS – dolasetron 6. ANTIFUNGALS – fluconazole, posaconazole, voriconazole 7. ANTIHISTAMINES – terfenadine, hydroxyzine, mizolastine 8. ANTIMALARIALS – artemether with lumefantrine, chloroquine, hydroxychloroquine, mefloquine 9. ANTIPROTOZOALS – pentamidine isetionate 10. ANTIPSYCHOTICS – atypicals, phenothiazines, pimozide 11. BETA-BLOCKERS – sotalol 12. BRONCHODILATORS – parenteral bronchodilators 13. CNS STIMULANTS – atomoxetine
Risk of ventricular arrhythmias, particularly torsades de pointes
Additive effect; these drugs prolong the Q-T interval. In addition, quinine inhibits CYP2D6mediated metabolism of procainamide
Avoid co-administration
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DRUGS TO TREAT INFECTIONS ANTIMALARIALS Quinine
Quinine inhibits CYP2D6 Watch for excessive narcotization
QUININE FLECAINIDE Quinine may ≠ flecainide levels Quinine inhibits CYP2D6-mediated metabolism of flecainide
The effect seems to be slight, but watch for flecainide toxicity; monitor PR and BP closely
QUININE MEXILETINE Quinine may ≠ mexiletine levels Quinine inhibits CYP2D6-mediated metabolism of mexiletine
Monitor PR and BP closely
QUININE ANTICANCER AND IMMUNOMODULATING DRUGS – PORFIMER
≠ risk of photosensitivity reactions Attributed to additive effects Avoid exposure of skin and eyes to direct sunlight for 30 days after porfimer therapy
QUININE ANTIMALARIALS – MEFLOQUINE Risk of seizures Additive effect Warn patients of the risk; patients should be advised to avoid driving while taking these drugs in combination
QUININE ANTIPARKINSON’S DRUGS – AMANTADINE
≠ side-effects ↓ renal excretion Monitor closely for confusion, disorientation, headache, dizziness and nausea
QUININE BETA-BLOCKERS Risk of ≠ plasma concentrations and effects of labetalol, metoprolol and propranolol; ≠ systemic effects of timolol eye drops
Quinine inhibits CYP2D6, which metabolizes these beta-blockers
Monitor BP at least weekly until stable
QUININE CARDIAC GLYCOSIDES – DIGOXIN
Plasma concentrations of digoxin may ≠ when it is co-administered with quinine
Uncertain, but seems to be due to ↓ non-renal (possibly biliary) excretion of digoxin
Monitor digoxin levels; watch for digoxin toxicity
QUININE H2 RECEPTOR BLOCKERS – CIMETIDINE
≠ efficacy and adverse effects of antimalarials
Inhibition of metabolism, some definitely via CYP3A4
Avoid co-administration
