chapter
Antifungal drugs
Pages 19

The combination of flucytosine and amphotericin may be used therapeutically. Watch for early features of flucytosine toxicity (gastrointestinal upset); monitor renal and liver function closely

AMPHOTERICIN ANTIPROTOZOALS – PENTAMIDINE ISETIONATE

Risk of arrhythmias Additive effect Monitor ECG closely

AMPHOTERICIN ANTIVIRALS

AMPHOTERICIN ADEFOVIR DIPIVOXIL Possible ≠ efficacy and side-effects Competition for renal excretion Monitor renal function weekly AMPHOTERICIN FOSCARNET SODIUM Possible ≠ nephrotoxicity Additive side-effect Monitor renal function closely AMPHOTERICIN NUCLEOSIDE REVERSE

TRANSCRIPTASE INHIBITORS – TENOFOVIR, ZIDOVUDINE

Possibly ≠ adverse effects with tenofovir and zidovudine

Additive toxicity Avoid if possible; otherwise monitor FBC and renal function (weekly). ↓ doses as necessary

AMPHOTERICIN CARDIAC GLYCOSIDES – DIGOXIN

Risk of digoxin toxicity due to hypokalaemia

Amphotericin may cause hypokalaemia

Monitor potassium levels closely. Monitor digoxin levels; watch for digoxin toxicity

AMPHOTERICIN DIURETICS – LOOP DIURETICS AND THIAZIDES

Risk of hypokalaemia Additive effect Monitor potassium closely

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DRUGS TO TREAT INFECTIONS ANTIFUNGAL DRUGS Azoles

FLUCONAZOLE, POSACONAZOLE, VORICONAZOLE

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. 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

KETOCONAZOLE ALISKIREN Aliskiren levels ≠ by ketoconazole

Uncertain Monitor BP and serum potassium at least weekly until stable

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Mechanism Precautions

parecoxib levels

Fluconazole inhibits CYP2C9mediated metabolism of celecoxib and parecoxib

Halve the dose of celecoxib, and start parecoxib at the lowest dose

FLUCONAZOLE, ITRACONAZOLE, KETOCONAZOLE, VORICONAZOLE

OPIOIDS 1. Ketoconazole ≠ effect of buprenorphine 2. Fluconazole and itraconazole ≠ effect of alfentanil 3. Fluconazole and possibly voriconazole ≠ effect of methadone; recognized pharmacokinetic effect but uncertain clinical significance

1. Ketoconazole ↓ CYP3A4mediated metabolism of buprenorphine 2. ↓ clearance of alfentanil 3. ↓ hepatic metabolism

1. The dose of buprenorphine needs to be ↓ (by up to 50%). 2. ↓ dose of alfentanil 3. Watch for ≠ effects of methadone

AZOLES ANTACIDS ↓ plasma concentration of itraconazole and ketoconazole, with risk of therapeutic failure

Itraconazole absorption in capsule form requires an acidic gastric environment and thus absorption would ↓

Separate administration of agents that ↓ gastric acidity by 1-2 hours. However, absorption of itraconazole liquid solution does not require an acidic environment and could be used instead; it does not need to be given with food. Fluconazole absorption is not pH dependent, and this is a suitable alternative

ITRACONAZOLE ANTIBIOTICS

ITRACONAZOLE, KETOCONAZOLE, VORICONAZOLE

CLARITHROMYCIN, CLOTRIMAZOLE, ERYTHROMYCIN, TELITHROMYCIN

≠ plasma concentrations of itraconazole and ketoconazole, and risk of toxic effects

These antibiotics are inhibitors of metabolism of itraconazole by CYP3A4. Erythromycin is a weaker inhibitor than clarithromycin. The role of clarithromycin and erythromycin as inhibitors of P-gp is not known with certainty. Ketoconazole is a potent inhibitor of P-gp

Monitor LFTs closely. Azithromycin is not affected

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DRUGS TO TREAT INFECTIONS ANTIFUNGAL DRUGS Azoles

VORICONAZOLE

inducer that can produce undetectable concentrations of ketoconazole

Rifampicin is a powerful inducer of CYP3A4 and other CYP isoenzymes. Rifabutin is a less powerful inducer but more potent than rifapentine. Rifapentine is an inducer of CYP3A4 and CYP2C8/9. Isoniazid is a known inhibitor of CYP2E1 and is likely to induce other CYP isoenzymes to varying degrees, usually in a time-dependent manner. Rifampicin is also a powerful inducer of P-gp, thus ↓ bioavailability of itraconazole

Avoid co-administration of ketoconazole or voriconazole with these drugs. Watch for inadequate therapeutic effects of itraconazole. Higher doses of itraconazole may not overcome this interaction, so consider use of less lipophilic fluconazole, which is less dependent on CYP metabolism. Avoid co-administration of posaconazole with rifabutin

VORICONAZOLE RIFABUTIN ≠ plasma concentrations of rifabutin, with risk of toxic effects of rifabutin (nausea, vomiting). Dangerous toxic effects such as leukopenia and thrombocytopenia may occur

Due to inhibition of metabolism of rifabutin by the CYP3A4 isoenzymes by voriconazole

Avoid concomitant use. If absolutely necessary, close monitoring of FBC, liver enzymes and examination of eyes for uveitis and corneal opacities are necessary

AZOLES ANTICANCER AND IMMUNOMODULATING DRUGS

ITRACONAZOLE, KETOCONAZOLE

BUSULFAN ≠ 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 1500 mol/min

Dose adjustments are necessary if concomitant administration is considered absolutely necessary; best, however, to avoid concomitant use. Monitor clinically for veno-occlusive disease and pulmonary toxicity in transplant patients. Monitor busulfan blood levels as an AUC below 1500 mol/min tends to prevent toxicity

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Mechanism Precautions KETOCONAZOLE, VORICONAZOLE

Due to ↓ metabolism of doxorubicin by CYP3A4 isoenzymes owing to inhibition of those enzymes

Monitor for ≠ myelosuppression, peripheral neuropathy, myalgias and fatigue

FLUCONAZOLE, ITRACONAZOLE, KETOCONAZOLE, VORICONAZOLE

ERLOTINIB ≠ erlotinib levels ↓ metabolism of erlotinib Avoid co-administration

FLUCONAZOLE, ITRACONAZOLE, KETOCONAZOLE, VORICONAZOLE

IFOSFAMIDE ↓ plasma concentrations of 4-hydroxyifosfamide, the active metabolite of ifosfamide, and risk of inadequate therapeutic response

Due to inhibition of the isoenzymatic conversion to active metabolites

Monitor clinically the efficacy of ifosfamide, and ≠ dose accordingly

FLUCONAZOLE, ITRACONAZOLE, KETOCONAZOLE, VORICONAZOLE

IMATINIB ≠ plasma concentrations of imatinib, with ≠ risk of toxicity (e.g. abdominal pain, constipation, dyspnoea) and neurotoxicity (e.g. taste disturbances, dizziness, headache, paraesthesia, peripheral neuropathy)

Due to inhibition of CYP3A4mediated metabolism of imatinib

Monitor for clinical efficacy and for the signs of toxicity listed, along with convulsions, confusion and signs of oedema (including pulmonary oedema). Monitor electrolytes, liver function and for cardiotoxicity

FLUCONAZOLE, ITRACONAZOLE, KETOCONAZOLE, VORICONAZOLE

IRINOTECAN ≠ plasma concentrations of SN-38 (AUC by 100%) and ≠ toxicity of irinotecan, e.g. diarrhoea, acute cholinergic syndrome, interstitial pulmonary disease

Due to inhibition of the metabolism of irinotecan by CYP3A4 isoenzymes by ketoconazole

Peripheral blood counts should be checked before each course of treatment. Monitor lung function. Recommendation is to ↓ dose of irinotecan by 25%

FLUCONAZOLE, ITRACONAZOLE, KETOCONAZOLE, VORICONAZOLE (POSSIBLY POSACONAZOLE)

VINCA ALKALOIDS – VINBLASTINE, VINCRISTINE, VINORELBINE

≠ adverse effects of vinblastine and vincristine

Inhibition of CYP3A4-mediated metabolism. Also inhibition of P-gp efflux of vinblastine

Monitor FBCs and watch for early features of toxicity (pain, numbness, tingling in the fingers and toes, jaw pain, abdominal pain, constipation, ileus). Consider selecting an alternative drug

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DRUGS TO TREAT INFECTIONS ANTIFUNGAL DRUGS Azoles

Due to inhibition of metabolism of toremifene by the CYP3A4 isoenzymes by ketoconazole

Clinical relevance is uncertain. Necessary to monitor for clinical toxicities

AZOLES – ITRACONAZOLE, KETOCONAZOLE, VORICONAZOLE

CICLOSPORIN ≠ plasma concentrations of ciclosporin, with risk of nephrotoxicity, myelosuppression, neurotoxicity and excessive immunosuppression, with risk of infection and post-transplant lymphoproliferative disease

Inhibition of CYP3A4-mediated metabolism of ciclosporin; these inhibitors vary in potency. Ketoconazole and itraconazole are classified as potent inhibitors. The effect is not clinically relevant with fluconazole

Avoid co-administration with itraconazole or ketoconazole. Consider an alternative azole but need to monitor plasma ciclosporin levels to prevent toxicity

AZOLES – FLUCONAZOLE, ITRACONAZOLE, KETOCONAZOLE, POSACONAZOLE, VORICONAZOLE

CORTICOSTEROIDS ≠ adrenal suppressive effects of corticosteroids, which may ≠ risk of infections and produce an inadequate response to stress scenarios

Due to inhibition of CYP3A4mediated metabolism of corticosteroids and inhibition of P-gp (≠ bioavailability of corticosteroids)

Monitor cortisol levels and warn patients to report symptoms such as fever and sore throat

AZOLES SIROLIMUS ≠ sirolimus levels Inhibition of metabolism of sirolimus

Avoid co-administration

AZOLES TACROLIMUS ≠ tacrolimus levels Inhibition of CYP3A4-mediated metabolism of tacrolimus

Monitor clinical effects closely; check levels

FLUCONAZOLE, ITRACONAZOLE, KETOCONAZOLE, MICONAZOLE, VORICONAZOLE

ANTICOAGULANTS – WARFARIN

≠ anticoagulant effect with azole antifungals. There have been cases of bleeding when topical miconazole (oral gel or pessaries) was used by patients on warfarin. Posaconazole may be a safer alternative

Itraconazole potently inhibits CYP3A4, which metabolizes both R-warfarin (also metabolized by CYP1A2) and the more active S-warfarin (also metabolized by CYP2C9)

Necessary to monitor the effects of warfarin closely (weekly INR) and to warn patients to report any symptoms of bleeding ➣ For signs and symptoms of overanticoagulation, see Clinical Features of Some Adverse Drug Interactions, Bleeding disorders

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Mechanism Precautions

Inhibition of metabolism via CYP1A2, CYP2D6 and CYP3A4

Consider alternative antifungals

AZOLES REBOXETINE Risk of ≠ reboxetine levels Possibly inhibition of CYP3A4mediated metabolism of reboxetine

Avoid co-administration

ITRACONAZOLE, KETOCONAZOLE, MICONAZOLE, FLUCONAZOLE, VORICONAZOLE

TCAs Possible ≠ plasma concentrations of TCAs

All TCAs are metabolized primarily by CYP2D6. Other pathways include CYP1A2 (e.g. amitriptyline, clomipramine, imipramine), CYP2C9 and CYP2C19 (e.g. clomipramine, imipramine). Ketoconazole and voriconazole are documented inhibitors of CYP2C19. Fluconazole and voriconazole are reported to inhibit CYP2C9

Warn patients to report ≠ side-effects of TCAs such as dry mouth, blurred vision and constipation, which may be an early sign of ≠ TCA levels. In this case, consider ↓ dose of TCA

AZOLES ANTIDIABETIC DRUGS

KETOCONAZOLE, FLUCONAZOLE, ITRACONAZOLE, VORICONAZOLE

NATEGLINIDE, REPAGLINIDE

Likely to ≠ plasma concentrations of repaglinide and ≠ risk of hypoglycaemic episodes

Due to inhibition of CYP3A4mediated metabolism. These drugs vary in potency as inhibitors (ketoconazole, itraconazole are potent inhibitors) and ≠ plasma concentrations will vary

ITRACONAZOLE, FLUCONAZOLE, MICONAZOLE, VORICONAZOLE

SULPHONYLUREAS ≠ risk of hypoglycaemic episodes Inhibition of CYP2C9-mediated metabolism of these sulphonylureas

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DRUGS TO TREAT INFECTIONS ANTIFUNGAL DRUGS Azoles

Inhibition of CYP3A4-mediated metabolism of aprepitant

Use with caution. Clinical significance unclear; monitor closely

FLUCONAZOLE, ITRACONAZOLE, KETOCONAZOLE, VORICONAZOLE

BARBITURATES ↓ azole levels, with risk of therapeutic failure

Barbiturates induce CYP3A4, which metabolizes itraconazole and the active metabolite of itraconazole. Primidone is metabolized to phenobarbitone

Watch for inadequate therapeutic effects, and ≠ dose of azole if due to interaction

MICONAZOLE BARBITURATES ≠ phenobarbital levels Inhibition of metabolism Be aware; watch for early features of toxicity (e.g. ≠ sedation)

ITRACONAZOLE, KETOCONAZOLE, MICONAZOLE, POSACONAZOLE, VORICONAZOLE

CARBAMAZEPINE, PHENYTOIN

↓ plasma concentrations of itraconazole and of its active metabolite, ketoconazole, posaconazole and voriconazole, with risk of therapeutic failure. ≠ phenytoin levels, but clinical significance uncertain. Carbamazepine plasma concentrations are also ≠

These azoles are highly lipophilic, and clearance is heavily dependent upon metabolism by CYP isoenzymes. Phenytoin and carbamazepine are powerful inducers of CYP3A4 and other CYP isoenzymes (CYP2C18/19, CYP1A2); the result is very low or undetectable plasma levels. Phenytoin extensively ↓ AUC of itraconazole by more than 90%. Inhibition of P-gp ≠ bioavailability of carbamazepine

Avoid co-administration of posaconazole or voriconazole with carbamazepine. Watch for inadequate therapeutic effects and ≠ dose of itraconazole. Higher doses of itraconazole may not overcome this interaction. Consider the use of less lipophilic fluconazole, which is less dependent on CYP metabolism. Necessary to monitor phenytoin and carbamazepine levels

ITRACONAZOLE ANTIFUNGALS

ITRACONAZOLE KETOCONAZOLE ≠ itraconazole levels, with risk of toxic effects

Ketoconazole is a potent inhibitor of the metabolism of itraconazole by the CYP3A4 and a potent inhibitor of P-gp, which is considered to ≠ bioavailability of itraconazole

Warn patients about toxic effects such as swelling around the ankles (peripheral oedema), shortness of breath, loss of appetite (anorexia) and yellow discoloration of the urine and eyes (jaundice). ↓ dose if due to interaction

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Mechanism Precautions

risk of therapeutic failure

Voriconazole is an inducer of CYP3A4

Watch for inadequate therapeutic effects, and ≠ dose of itraconazole if due to interaction. Higher doses of itraconazole may not overcome this interaction, so consider the use of less lipophilic fluconazole, which is less dependent on CYP metabolism

AZOLES ANTIHISTAMINES

AZOLES MIZOLASTINE ≠ mizolastine levels Inhibition of metabolism of mizolastine

Avoid co-administration

KETOCONAZOLE, POSACONAZOLE

LORATIDINE ≠ loratidine levels Inhibition of cytochrome P450, P-gp or both

Avoid co-administration

AZOLES – ITRACONAZOLE ANTIHYPERTENSIVES AND HEART FAILURE DRUGS – VASODILATOR ANTIHYPERTENSIVES – bosentan

Azole antifungals ≠ bosentan levels

Azoles inhibit CYP3A4 and CYP2C9

Monitor LFTs closely

AZOLES ANTIMIGRAINE DRUGS – 5-HT1 AGONISTS

≠ levels of almotriptan and eletriptan

Inhibited metabolism Avoid co-administration

ITRACONAZOLE, KETOCONAZOLE

ANTIMUSCARINICS 1. ↓ ketoconazole levels 2. ≠ darifenacin, solifenacin and tolterodine levels

1. ↓ absorption 2. Inhibited metabolism

1. Watch for poor response to ketoconazole 2. Avoid co-administration of ketoconazole and these antimuscarinics

KETOCONAZOLE ANTIOBESITY DRUGS – RIMONABANT

≠ rimonabant levels Ketoconazole inhibits CYP3A4mediated metabolism of rimonabant

Avoid co-administration

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DRUGS TO TREAT INFECTIONS ANTIFUNGAL DRUGS Azoles

ritonavir (with or without lopinavir). Conversely, indinavir, ritonavir and saquinavir levels ≠ by itraconazole and ketoconazole

Inhibition of, or competition for, CYP3A4-mediated metabolism

Use itraconazole with caution and monitor for adverse effects. No dose adjustment is recommended for doses400 mg/day of ketoconazole

VORICONAZOLE RITONAVIR ↓ efficacy of voriconazole ↓ plasma levels Avoid co-administration if the dose of ritonavir is 400 mg twice a day or greater. Avoid combining low-dose ritonavir (100 mg twice a day) unless benefits outweigh risks

FLUCONAZOLE, VORICONAZOLE

NNRTIs Possible ↓ efficacy of azole ≠ CYP3A4-mediated metabolism Avoid co-administration

ITRACONAZOLE, KETOCONAZOLE

DIDANOSINE Possibly ↓ efficacy of ketoconazole and itraconazole with buffered didanosine

Absorption of the ketoconazole and itraconazole may be ↓ by the buffered didanosine formulation, which raises gastric pH

Give the ketoconazole and itraconazole 2 hours before or 6 hours after didanosine. Alternatively, consider using the enteric-coated formulation of didanosine, which does not have to be given separately

FLUCONAZOLE ZIDOVUDINE ≠ zidovudine levels Inhibition of metabolism Avoid co-administration

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Mechanism Precautions

KETOCONAZOLE, VORICONAZOLE

CHLORDIAZEPOXIDE, DIAZEPAM, LORAZEPAM, MIDAZOLAM, OXAZEPAM, TEMAZEPAM

BZDs, with ≠, with risk of adverse effects. These risks are greater following intravenous administration of midazolam compared with oral midazolam

Itraconazole and ketoconazole are potent inhibitors of phase I metabolism (oxidation and functionalization) of these BZDs by CYP3A4. In addition, the more significant ≠ in plasma concentrations following oral midazolam (15 times compared with five times following intravenous use) indicates that the inhibition of P-gp by ketoconazole is important following oral administration

Aim to avoid co-administration. If coadministration is necessary, always start with a low dose and monitor effects closely. Consider use of alternative BZDs that undergo predominantly phase II metabolism by glucuronidation, e.g. flurazepam, quazepam. Fluconazole and posaconazole are unlikely to cause this interaction

ITRACONAZOLE BUSPIRONE ≠ buspirone levels Inhibition of CYP3A4-mediated metabolism

Warn patients to be aware of additional sedation

KETOCONAZOLE ZALEPLON, ZOLPIDEM, ZOPICLONE

≠ zolpidem levels reported; likely to occur with zaleplon and zopiclone

Inhibition of CYP3A4-mediated metabolism

Warn patients of the risk of ≠ sedation

ITRACONAZOLE, KETOCONAZOLE, POSACONAZOLE

BRONCHODILATORS – THEOPHYLLINE

≠ theophylline levels, with risk of toxicity, with itraconazole. Unpredictable effect on theophylline levels with ketoconazole

Theophylline is primarily metabolized by CYP1A2. Although azoles are best known as inhibitors of CYP3A4, they also inhibit other CYP isoenzymes to varying degrees

If concurrent use is necessary, monitor theophylline levels at the initiation of itraconazole therapy or on discontinuing therapy. Terbinafine may be a safer alternative

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DRUGS TO TREAT INFECTIONS ANTIFUNGAL DRUGS Azoles

POSACONAZOLE, VORICONAZOLE

itraconazole and ketoconazole. Risk of ≠ verapamil levels with ketoconazole and itraconazole. Itraconazole and possibly posaconazole may ≠ diltiazem levels

The azoles are potent inhibitors of CYP3A4 isoenzymes, which metabolize calcium channel blockers. They also inhibit CYP2C9-mediated metabolism of verapamil. Ketoconazole and itraconazole both inhibit intestinal P-gp, which may ≠ bioavailability of verapamil. Diltiazem is mainly a substrate of CYP3A5 and CYP3A5P1, which are inhibited by itraconazole. 75% of the metabolism of diltiazem occurs in the liver and the rest in the intestine. Diltiazem is a substrate of P-gp (also an inhibitor but unlikely to be significant at therapeutic doses), which is inhibited by itraconazole, resulting in ≠ bioavailability of diltiazem

Monitor PR, BP and ECG, and warn patents to watch for symptoms/signs of heart failure

ITRACONAZOLE CARDIAC GLYCOSIDES – DIGOXIN

Itraconazole may cause ≠ plasma levels of digoxin; cases of digoxin toxicity have been reported

Itraconazole inhibits P-gp-mediated renal clearance and ≠ intestinal absorption of digoxin

Monitor digoxin levels; watch for digoxin toxicity

ITRACONAZOLE, KETOCONAZOLE

CNS STIMULANTS – MODAFINIL

≠ plasma concentrations of modafinil, with risk of adverse effects

Due to inhibition of CYP3A4, which has a partial role in the metabolism of modafinil

Be aware. Warn patients to report dose-related adverse effects, e.g. headache, anxiety

KETOCONAZOLE DIURETICS – POTASSIUMSPARING DIURETICS AND ALDOSTERONE ANTAGONISTS

≠ eplerenone levels Inhibition of metabolism Avoid co-administration

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Precautions

Avoid co-administration. If absolutely necessary, advise patients to discontinue treatment immediately if numbness and tingling of the extremities are felt

ITRACONAZOLE GRAPEFRUIT JUICE Possibly ↓ efficacy ↓ absorption possibly by inhibition of intestinal CYP3A4, affecting P-gp or lowering duodenal pH

Clinical significance is unknown. The effect of the interaction may vary between capsules and oral liquid preparations

ITRACONAZOLE, KETOCONAZOLE, MICONAZOLE, POSACONAZOLE

H2 RECEPTOR BLOCKERS

↓ plasma concentrations and risk of treatment failure

↓ absorption of these antifungals as ≠ gastric pH

Avoid concomitant use. If unable to avoid combination, take H2 blockers at least 2-3 hours after the antifungal. Use an alternative antifungal or separate doses by at least 2 hours and give with an acidic drink, e.g. a carbonated drink; ≠ dose of antifungal may be required

FLUCONAZOLE, ITRACONAZOLE, KETOCONAZOLE

IVABRADINE ≠ levels with ketoconazole and possibly fluconazole and itraconazole

Uncertain Avoid co-administration

FLUCONAZOLE, ITRACONAZOLE, KETOCONAZOLE, POSACONAZOLE

LIPID-LOWERING DRUGS – STATINS

Azoles markedly ≠ atorvastatin, simvastatin (both with cases of myopathy reported) and possibly pravastatin. These effects are less likely with fluvastatin and rosuvastatin, although fluconazole may cause moderate rises in their levels

Itraconazole and ketoconazole inhibit CYP3A4-mediated metabolism of these statins; they also inhibit intestinal P-gp, which ≠ bioavailability of statins. Itraconazole may block the transport of atorvastatin due to inhibition of the OATP1B1 enzyme system. Some manufacturers suggest that the small ≠ in plasma levels of pravastatin may be due to ≠ absorption. Voriconazole is an inhibitor of CYP2C9. Fluconazole inhibits CYP2C9 and CYP3A4

Avoid co-administration of simvastatin and atorvastatin with azole antifungals. Care should be taken with coadministration of other statins and azoles. Although fluvastatin and rosuvastatin may be considered as alternatives, consider ↓ dose of statin and warn patients to report any features of rhabdomyolysis. Check LFTs and CK regularly

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DRUGS TO TREAT INFECTIONS ANTIFUNGAL DRUGS Azoles

POSACONAZOLE, VORICONAZOLE

disturbances 2-3 weeks after the start of the pill cycle, delayed bleeding and pregnancy. Effects of either or both of oestrogen excess and progestogen excess may occur (migraine headaches, thromboembolic episodes, breast tenderness, bloating, weight gain)

diol, a common constituent, as well as progestogens are substrates of CYP3A4 that are inhibited by itraconazole. The inhibition of ethinylestradiol and progestogens could lead to effects of oestrogen and progestogens excess. Triazole antifungals inhibit biotransformation of steroids, and such an ≠ may cause a delay of withdrawal bleeding

Due to the complex metabolic pathways of oral contraceptives, dependent on constituents, doses and the reported adverse effects during concomitant use, it is advisable to avoid use of azole antifungals or advise alternative methods of contraception

KETOCONAZOLE PARASYMPATHOMIME TICS – GALANTAMINE

≠ galantamine levels Inhibition of CYP3A4-mediated metabolism of galantamine

Monitor PR and BP closely, watching for bradycardia and hypotension

FLUCONAZOLE, ITRACONAZOLE, KETOCONAZOLE, MICONAZOLE

PERIPHERAL VASODILATORS – CILOSTAZOL

Fluconazole, itraconazole, ketoconazole and miconazole ≠ cilostazol levels

These azoles inhibit CYP3A4-mediated metabolism of cilostazol

Avoid co-administration

AZOLES PHOSPHODIESTERASE TYPE 5 INHIBITORS

≠ sildenafil, tadalafil, and vardenafil levels

Inhibition of metabolism ↓ dose of these phosphodiesterase inhibitors

AZOLES PROTON PUMP INHIBITORS

ITRACONAZOLE, KETOCONAZOLE

PROTON PUMP INHIBITORS

Possible ↓ efficacy of the antifungal

↓ absorption Monitor for ↓ efficacy; ≠ dose may be required. Separate doses by at least 2 hours and give ketoconazole with a cola drink

VORICONAZOLE OMEPRAZOLE Possible ≠ efficacy and adverse effects of both drugs

1. Inhibition of voriconazole metabolism via CYP2C19 and CYP3A4 2. Inhibition of metabolism of omeprazole

1. No dose adjustment of voriconazole is recommended 2. Halve the omeprazole dose

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Mechanism Precautions

prolongation of the Q-T interval

CYP3A4 is the major enzyme involved in the elimination of tolterodine in individuals with deficient CYP2D6 activity (poor metabolizers). Inhibition of CYP3A4 by triazoles in such individuals could cause dangerous ≠ tolterodine levels

Avoid co-administration

CASPOFUNGIN

CASPOFUNGIN ANTIBIOTICS – RIFAMPICIN ↓ caspofungin levels, with risk of therapeutic failure

Induction of caspofungin metabolism

≠ dose of caspofungin to 70 mg daily

CASPOFUNGIN ANTICANCER AND IMMUNOMODULATING DRUGS

CASPOFUNGIN CICLOSPORIN 1. ↓ plasma concentrations of ciclosporin, with risk of transplant rejection 2. Enhanced toxic effects of caspofungin and ≠ alanine transaminase levels

1. Due to induction of metabolism of ciclosporin by these drugs. The potency of induction varies 2. Uncertain

1. Monitor for signs of rejection of transplants. Monitor ciclosporin levels to ensure adequate therapeutic concentrations and ≠ dose when necessary 2. Monitor LFTs

CASPOFUNGIN DEXAMETHASONE ↓ caspofungin levels, with risk of therapeutic failure

Induction of caspofungin metabolism

≠ dose of caspofungin to 70 mg daily

CASPOFUNGIN TACROLIMUS ↓ tacrolimus levels Induction of CYP3A4-mediated metabolism of tacrolimus

Avoid co-administration

CASPOFUNGIN ANTIEPILEPTICS – CARBAMAZEPINE, PHENYTOIN

↓ caspofungin levels, with risk of therapeutic failure

Induction of caspofungin metabolism

≠ dose of caspofungin to 70 mg daily

CASPOFUNGIN ANTIVIRALS – EFAVIRENZ, NEVIRAPINE

↓ caspofungin levels, with risk of therapeutic failure

Induction of caspofungin metabolism

≠ dose of caspofungin to 70 mg daily

D R

U G

STO TR

EA TIN

FEC TIO

N S

A N

TIFU N

G A

LD R

U G

S577

DRUGS TO TREAT INFECTIONS ANTIFUNGAL DRUGS Griseofulvin

DRUGS – CYTARABINE

Uncertain Watch for poor response to flucytosine

FLUCYTOSINE ANTIFUNGALS – AMPHOTERICIN

≠ flucytosine levels, with risk of toxic effects

Amphotericin causes ↓ renal excretion of flucytosine and ≠ cellular uptake

The combination of flucytosine and amphotericin may be used therapeutically. Watch for early features of flucytosine toxicity (gastrointestinal upset); monitor renal and liver function closely

FLUCYTOSINE ANTIVIRALS – ZIDOVUDINE Possibly ≠ adverse effects with zidovudine

Additive toxicity Avoid if possible; otherwise monitor FBC and renal function (weekly). ↓ doses as necessary

GRISEOFULVIN

GRISEOFULVIN ALCOHOL Disulfiram-like reaction can occur Uncertain Warn patients not to drink alcohol while taking griseofulvin

GRISEOFULVIN ANTICANCER AND IMMUNOMODULATING DRUGS – CICLOSPORIN

↓ plasma concentrations of ciclosporin (may be as much as 40%) and risk of rejection in patients who have received transplants

Induction of ciclosporin metabolism

Monitor ciclosporin levels closely

GRISEOFULVIN ANTICOAGULANTS – ORAL Possible ↓ anticoagulant effect coumarins and phenindione

Unknown Necessary to monitor the effects of warfarin closely (weekly INR) and to warn patients to report any symptoms of bleeding ➣ For signs and symptoms of overanticoagulation, see Clinical Features of Some Adverse Drug Interactions, Bleeding disorders

D R

U G

STO TR

EA TIN

FEC TIO

N S

A N

TIFU N

G A

LD R

U G

S

Mechanism Precautions

Inhibition of metabolism Warn patients to report any ≠ side-

effects of TCAs such as dry mouth, blurred vision and constipation, which may be an early sign of ≠ TCA levels. In this case, consider ↓ dose of TCA

GRISEOFULVIN ANTIDIABETIC DRUGS – REPAGLINIDE

↓ repaglinide levels Hepatic metabolism induced Watch for and warn patients about hypoglycaemia ➣ For signs and symptoms of hypoglycaemia, see Clinical Features of Some Adverse Drug Interactions, Hypoglycaemia

GRISEOFULVIN ANTIEPILEPTICS – PHENOBARBITONE, PRIMIDONE

↓ griseofulvin levels ↓ absorption Although the effect of ↓ plasma concentrations on therapeutic effect has not been established, concurrent use is preferably avoided

GRISEOFULVIN BRONCHODILATORS – THEOPHYLLINE

≠ theophylline levels Inhibition of metabolism of theophylline

Uncertain clinical significance. Watch for early features of theophylline toxicity

GRISEOFULVIN OESTROGENS ↓ oestrogen levels, which may lead to failure of contraception

Induction of metabolism of oestrogens

Long-term use of griseofulvin is likely to ↓ effectiveness of oral contraceptives. Patients should be advised to use an alternative method of contraception during griseofulvin therapy and for 1 month after its discontinuation

D R

U G

STO TR

EA TIN

FEC TIO

N S

A N

TIFU N

G A

LD R

U G

S579

DRUGS TO TREAT INFECTIONS ANTIFUNGAL DRUGS Terbinafine

menorrhagia

Induction of the CYP-mediated metabolism of oestrogens

Long-term use of griseofulvin is likely to ↓ effectiveness of oral contraceptives. Patients should be advised to use an alternative method of contraception during griseofulvin therapy and for 1 month after its discontinuation

TERBINAFINE

TERBINAFINE ANTIBIOTICS – RIFAMPICIN ↓ terbinafine levels Induction of metabolism Watch for poor response to terbinafine

TERBINAFINE ANTIDEPRESSANTS – IMIPRAMINE, NORTRIPTYLINE

Possible ≠ plasma concentrations of TCAs

Terbinafine strongly inhibits CYP2D6-mediated metabolism of nortriptyline

Warn patients to report ≠ side-effects of TCAs such as dry mouth, blurred vision and constipation, which may be an early sign of ≠ TCA levels. In this case, consider ↓ dose of TCA

TERBINAFINE H2 RECEPTOR BLOCKERS – CIMETIDINE

≠ efficacy and adverse effects of terbinafine

≠ bioavailability Consider alternative acid suppression or monitor more closely and consider ↓ dose

TERBINAFINE OESTROGENS ↓ oestrogen levels, which may lead to failure of contraception

Alteration of the bacterial flora necessary for recycling ethinylestradiol from the large bowel

Patients should be advised to use an alternative method of contraception during terbinafine therapy and for 1 month after its discontinuation

TERBINAFINE PROGESTOGENS ↓ progestogen levels, which may lead to a failure of contraception or poor response to treatment of menorrhagia

Induction of the CYP-mediated metabolism of oestrogens

Patients should be advised to use an alternative method of contraception during terbinafine therapy and for 1 month after its discontinuation