chapter
Antimalarials
Pages 12

Avoid co-administration

D R

U G

STO TR

EA TIN

FEC TIO

N S

A N

TIM A

LA R

IA LS581

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

D R

U G

STO TR

EA TIN

FEC TIO

N S

A N

TIM A

LA R

IA LS

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

D R

U G

STO TR

EA TIN

FEC TIO

N S

A N

TIM A

LA R

IA LS583

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

D R

U G

STO TR

EA TIN

FEC TIO

N S

A N

TIM A

LA R

IA LS

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

D R

U G

STO TR

EA TIN

FEC TIO

N S

A N

TIM A

LA R

IA LS585

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

D R

U G

STO TR

EA TIN

FEC TIO

N S

A N

TIM A

LA R

IA LS

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)

D R

U G

STO TR

EA TIN

FEC TIO

N S

A N

TIM A

LA R

IA LS587

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

D R

U G

STO TR

EA TIN

FEC TIO

N S

A N

TIM A

LA R

IA LS

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

D R

U G

STO TR

EA TIN

FEC TIO

N S

A N

TIM A

LA R

IA LS589

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

D R

U G

STO TR

EA TIN

FEC TIO

N S

A N

TIM A

LA R

IA LS

Mechanism Precautions

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

D R

U G

STO TR

EA TIN

FEC TIO

N S

A N

TIM A

LA R

IA LS591

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