ABSTRACT
Be aware that the effects of alfentanil (especially when given as an infusion) may be prolonged by erythromycin
AZITHROMYCIN ANTACIDS ↓ levels of these antibiotics ↓ absorption Take azithromycin at least 1 hour before or 2 hours after an antacid. Take these cephalosporins at least 2 hours after an antacid. Separate quinolones and antacids by 2-6 hours. Separate tetracyclines and antacids by 2-3 hours
MACROLIDES ANTIBIOTICS
MACROLIDES RIFABUTIN ≠ rifabutin levels Inhibition of CYP3A4-mediated metabolism of rifabutin
Watch for early features of toxicity of rifabutin (warn patients to report painful eyes)
CLARITHROMYCIN, TELITHROMYCIN
RIFAMPICIN ↓ levels of these macrolides Rifampicins induce metabolism of these macrolides
Avoid co-administration for up to 2 weeks after stopping rifampicin
MACROLIDES ANTICANCER AND IMMUNOMODULATING DRUGS
CLARITHROMYCIN, ERYTHROMYCIN
BUSULFAN ≠ plasma concentrations of busulfan and ≠ risk of toxicity of busulfan such as veno-occlusive disease and pulmonary fibrosis
Macrolides are inhibitors of CYP3A4. Busulfan clearance may be ↓ by 25%, and the AUC of busulfan may ≠ by 1500 mol/L
Monitor clinically for veno-occlusive disease and pulmonary toxicity in transplant patients. Monitor busulfan blood levels as AUCs below 1500 mol/L per minute tends to prevent toxicity
ERYTHROMYCIN DOCETAXEL ≠ docetaxel levels Inhibition of CYP3A4-mediated metabolism of docetaxel is metabolized by enzymes that are moderately inhibited by erythromycin, leading to ≠ levels and possible toxicity
Cautious use or consider use of azithromycin, which has little effect on CYP3A4 and therefore is not expected to interact with docetaxel
DRUGS TO TREAT INFECTIONS ANTIBIOTICS – MACROLIDES
Due to ↓ metabolism of doxorubicin by CYP3A4 isoenzymes due to inhibition of those enzymes
Monitor for ≠ myelosuppression, peripheral neuropathy, myalgias and fatigue
CLARITHROMYCIN, ERYTHROMYCIN
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
CLARITHROMYCIN, ERYTHROMYCIN
IMATINIB ≠ imatinib levels with ≠ risk of toxicity (e.g. abdominal pain, constipation, dyspnoea) and of 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, signs of oedema (including pulmonary oedema). Monitor electrolytes, liver function and for cardiotoxicity
CLARITHROMYCIN, ERYTHROMYCIN
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 macrolides
Peripheral blood counts should be checked before each course of treatment. Monitor lung function. Recommendation is to ↓ dose of irinotecan by 25%
CLARITHROMYCIN, ERYTHROMYCIN
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. 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
CLARITHROMYCIN, ERYTHROMYCIN
TOREMIFENE ≠ plasma concentrations of toremifene with clarithromycin and erythromycin
Due to inhibition of metabolism of toremifene by the CYP3A4 isoenzymes
Clinical relevance is uncertain. Necessary to monitor for clinical toxicities
D R
U G
STO TR
EA TIN
FEC TIO
N S
A N
TIB IO
TIC S-M
A C
R O
LID ES
D R
U G
STO TR
EA TIN
FEC TIO
N S
A N
TIB IO
TIC S-M
A C
R O
LID ES
Mechanism Precautions
ERYTHROMYCIN, TELITHROMYCIN
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. Clarithromycin and telithromycin are classified as potent inhibitors
Avoid co-administration with clarithromycin and telithromycin. Consider alternative antibiotics but need to monitor plasma ciclosporin levels to prevent toxicity
CLARITHROMYCIN, ERYTHROMYCIN
CORTICOSTEROIDS ≠ adrenal suppressive effects of corticosteroids, which may ≠ risk of infections and produce an inadequate response to stress scenarios
Due to inhibition of metabolism of corticosteroids
Monitor cortisol levels and warn patients to report symptoms such as fever and sore throat
CLARITHROMYCIN, ERYTHROMYCIN
SIROLIMUS ≠ sirolimus levels Inhibition of metabolism of sirolimus
Avoid co-administration
MACROLIDES TACROLIMUS ≠ plasma concentrations of tacrolimus, with risk of toxic effect
Clarithromycin, erythromycin and telithromycin inhibit CYP3A4mediated metabolism of tacrolimus. Azithromycin, if at all, mildly inhibits CYP3A4; a marked ≠ in tacrolimus levels is attributed to inhibition of P-gp
Be aware and monitor tacrolimus plasma concentrations
MACROLIDES ANTICOAGULANTS – ORAL Occasional episodes of ≠ anticoagulant effect
Uncertain at present Monitor INR every 2-3 days
MACROLIDES ANTIDEPRESSANTS
ERYTHROMYCIN MAOIs – PHENELZINE Report of fainting and severe hypotension on initiation of erythromycin
Attributed to ≠ absorption of phenelzine due to rapid gastric emptying caused by erythromycin
Be aware
D R
U G
STO TR
EA TIN
FEC TIO
N S
A N
TIB IO
TIC S-M
A C
R O
LID ES519
DRUGS TO TREAT INFECTIONS ANTIBIOTICS – MACROLIDES
Possibly inhibition of CYP3A4mediated metabolism of reboxetine
Avoid co-administration
TELITHROMYCIN ST JOHN’S WORT ↓ telithromycin levels Due to induction of CYP3A4mediated metabolism of telithromycin
Avoid co-administration for up to 2 weeks after stopping St John’s wort
ERYTHROMYCIN, CLARITHROMYCIN, TELITHROMYCIN
ANTIDIABETIC DRUGS – REPAGLINIDE
Likely to ≠ plasma concentrations of repaglinide and ≠ risk of hypoglycaemic episodes. ≠ risk of gastrointestinal side-effects with clarithromycin
Due to inhibition of CYP3A4 isoenzymes, which metabolize repaglinide. These drugs vary in potency as inhibitors (clarithromycin is a potent inhibitor) and ≠ plasma concentrations varies. Clarithromycin ≠ plasma concentrations by 60%. However, the alternative pathway – CYP2C8 – is unaffected by these inhibitors
MACROLIDES ANTIEMETICS – APREPITANT
≠ aprepitant levels Inhibition of CYP3A4-mediated metabolism of aprepitant
Use with caution. Clinical significance unclear; monitor closely
MACROLIDES ANTIEPILEPTICS
TELITHROMYCIN BARBITURATES ↓ levels of these drugs, with risk of therapeutic failure
Induction of hepatic metabolism 1. Avoid co-administration of telithromycin for up to 2 weeks after stopping phenobarbital 2. With the other drugs, monitor for ↓ clinical efficacy and ≠ dose as required
TELITHROMYCIN CARBAMAZEPINE ↓ levels of these drugs, with risk of therapeutic failure
Induction of hepatic metabolism 1. Avoid co-administration of telithromycin for up to 2 weeks after stopping carbamazepine 2. With the other drugs, monitor for ↓ clinical efficacy and ≠ dose as required
D R
U G
STO TR
EA TIN
FEC TIO
N S
A N
TIB IO
TIC S-M
A C
R O
LID ES
Mechanism Precautions
Inhibition of metabolism Monitor carbamazepine levels
TELITHROMYCIN PHENYTOIN ↓ levels of these drugs, with risk of therapeutic failure
Induction of hepatic metabolism 1. Avoid co-administration of telithromycin for up to 2 weeks after stopping phenytoin 2. With the other drugs, monitor for ↓ clinical efficacy and ≠ dose as required
CLARITHROMYCIN PHENYTOIN ≠ phenytoin levels Inhibited metabolism Monitor phenytoin levels ERYTHROMYCIN VALPROATE ≠ valproate levels Inhibited metabolism Monitor levels
CLARITHROMYCIN, ERYTHROMYCIN, TELITHROMYCIN
ANTIFUNGALS – ITRACONAZOLE, KETOCONAZOLE, VORICONAZOLE
≠ plasma concentrations of itraconazole, ketoconazole and voriconazole, and risk of toxic effects
These antibiotics are inhibitors of metabolism of itraconazole by the 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 does not cause this effect
ERYTHROMYCIN, CLARITHROMYCIN
ANTIGOUT DRUGS – COLCHICINE
Cases of colchicine toxicity when macrolides added
Uncertain; macrolides may inhibit hepatic metabolism of colchicine. Clarithromycin and erythromycin both inhibit intestinal P-gp, which may ≠ bioavailability of colchicine
Monitor FBC and renal function closely
MACROLIDES ANTIMIGRAINE DRUGS
MACROLIDES ERGOT DERIVATIVES ≠ ergotamine/methysergide levels, with risk of toxicity
Inhibition of CYP3A4-mediated metabolism of the ergot derivatives
Avoid co-administration
D R
U G
STO TR
EA TIN
FEC TIO
N S
A N
TIB IO
TIC S-M
A C
R O
LID ES521
DRUGS TO TREAT INFECTIONS ANTIBIOTICS – MACROLIDES
heaviness, pressure or tightness of any part of body including the throat and chest, dizziness
Almotriptan is metabolized mainly by CYP3A4 isoenzymes. Most CYP isoenzymes are inhibited by clarithromycin to varying degrees, and since there is an alternative pathway of metabolism by MAOA, the toxicity responses will vary between individuals
Avoid co-administration
CLARITHROMYCIN, ERYTHROMYCIN
ANTIMUSCARINICS – TOLTERODINE
≠ tolterodine levels Inhibition of CYP3A4-mediated metabolism
Avoid co-administration (manufacturers’ recommendation)
ERYTHROMYCIN ANTIPARKINSON’S DRUGS – BROMOCRIPTINE, CABERGOLINE
≠ bromocriptine and cabergoline levels
Inhibition of metabolism Monitor BP closely and watch for early features of toxicity (nausea, headache, drowsiness)
ERYTHROMYCIN ANTIPSYCHOTICS – CLOZAPINE
≠ clozapine levels, with risk of clozapine toxicity
Clozapine is metabolized by CYPIA2, which is moderately inhibited by erythromycin. Erythromycin is a potent inhibitor of CYP3A4, which has a minor role in the metabolism of clozapine. This may lead to ↓ clearance and therefore ≠ levels of clozapine
Cautious use advised
MACROLIDES ANTIVIRALS
CLARITHROMYCIN NNRTIs 1. ↓ efficacy of clarithromycin but ≠ efficacy and adverse effects of the active metabolite 2. A rash occurs in 46% of patients when efavirenz is given with clarithromycin
1. Uncertain: possibly due to altered CYP3A4-mediated metabolism 2. Uncertain
1. Clinical significance unknown; no dose adjustment is recommended when clarithromycin is co-administered with nevirapine, but monitor LFTs and activity against Mycobacterium avium intracellulare complex closely 2. Consider alternatives to clarithromycin for patients on efavirenz
D R
U G
STO TR
EA TIN
FEC TIO
N S
A N
TIB IO
TIC S-M
A C
R O
LID ES
Mechanism Precautions
Possibly involves altered P-gp transport
Watch for signs of azithromycin toxicity
CLARITHROMYCIN, ERYTHROMYCIN
PROTEASE INHIBITORS Possibly ≠ adverse effects of macrolide with atazanavir, ritonavir (with or without lopinavir) and saquinavir
Inhibition of CYP3A4-and possibly CYP1A2-mediated metabolism. Altered transport via P-gp may be involved. Amprenavir and indinavir are also possibly ≠ by erythromycin
Consider alternatives unless there is Mycobacterium avium intracellulare infection; if combined, ↓ dose by 50% (75% in the presence of renal failure with a creatinine clearance of 30 mL/min)
MACROLIDES ANXIOLYTICS AND HYPNOTICS
ERYTHROMYCIN, CLARITHROMYCIN, TELITHROMYCIN
MIDAZOLAM, TRIAZOLAM, POSSIBLY ALPRAZOLAM
≠ BZD levels Inhibition of CYP3A4-mediated metabolism
↓ dose of BZD by 50%; warn patients not to perform skilled tasks such as driving for at least 10 hours after the dose of BZD
MACROLIDES BUSPIRONE ≠ buspirone levels Inhibition of CYP3A4-mediated metabolism
Warn patients to be aware of additional sedation
MACROLIDES BRONCHODILATORS
MACROLIDES LEUKOTRIENE RECEPTOR ANTAGONISTS – ZAFIRLUKAST
↓ zafirlukast levels Induction of metabolism Watch for poor response to zafirlukast
AZITHROMYCIN, CLARITHROMYCIN, ERYTHROMYCIN
THEOPHYLLINE 1. ≠ theophylline levels 2. Possibly ↓ erythromycin levels when given orally
1. Inhibition of CYP2D6-mediated metabolism of theophylline (macrolides and quinolones – isoniazid not known) 2. ↓ bioavailability; uncertain mechanism
1. Monitor theophylline levels before, during and after co-administration 2. Consider an alternative macrolide
D R
U G
STO TR
EA TIN
FEC TIO
N S
A N
TIB IO
TIC S-M
A C
R O
LID ES523
DRUGS TO TREAT INFECTIONS ANTIBIOTICS – MACROLIDES
adverse effects of verapamil (bradycardia and ↓ BP) with both erythromycin and clarithromycin
Erythromycin inhibits CYP3A4metabolism of felodipine and verapamil. Clarithromycin and erythromycin inhibit intestinal P-gp, which may ≠ bioavailability of verapamil
Monitor PR and BP closely; watch for bradycardia and ↓ BP. Consider ↓ dose of calcium channel blocker during macrolide therapy
MACROLIDES CARDIAC GLYCOSIDES – DIGOXIN
Digoxin concentrations may be ≠ by the macrolides
Uncertain; postulated that macrolides inhibit P-gp in both the intestine (≠ bioavailability) and kidney (↓ clearance). It is possible that alterations in intestinal flora may also have a role
Monitor digoxin levels; watch for digoxin toxicity
CLARITHROMYCIN, TELITHROMYCIN
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
ERYTHROMYCIN DIURETICS – POTASSIUMSPARING
≠ eplerenone results in ≠ risk of hypotension and hyperkalaemia
Eplerenone is primarily metabolized by CYP3A4; there are no active metabolites. Erythromycin moderately inhibits CYP3A4, leading to ≠ levels of eplerenone
Eplerenone dosage should not exceed 25 mg daily
ERYTHROMYCIN H2 RECEPTOR BLOCKERS – CIMETIDINE
≠ efficacy and adverse effects of erythromycin, including hearing loss
≠ bioavailability Consider an alternative antibiotic, e.g. clarithromycin. Deafness was reversible with cessation of erythromycin
MACROLIDES IVABRADINE 1. Risk of arrhythmias with erythromycin 2. Possible ≠ levels with clarithromycin and telithromycin
1. Additive effect 2. Uncertain Avoid co-administration
Mechanism Precautions
SIMVASTATIN
atorvastatin and simvastatin; the risk of myopathy ≠10x when erythromycin is co-administered with a statin
Macrolides inhibit CYP3A4mediated metabolism of atorvastatin and simvastatin. Also, erythromycin and clarithromycin inhibit intestinal P-gp, which may ≠ bioavailability of statins
Avoid co-administration of macrolides with atorvastatin or simvastatin (temporarily stop the statin if the patient needs macrolide therapy). Manufacturers also recommend that patients are warned to look for the early signs of rhabdomyolysis when other statins are co-ingested with macrolides
ERYTHROMYCIN ROSUVASTATIN ↓ rosuvastatin levels with erythromycin
Uncertain Avoid chronic co-administration
ERYTHROMYCIN OESTROGENS Reports of ↓ contraceptive effect Possibly alteration of the bacterial flora necessary for recycling ethinylestradiol from the large bowel, although not certain in every case
Advise patients to use additional contraception for the period of antibiotic intake and for 1 month after stopping the antibiotic
ERYTHROMYCIN PARASYMPATHOMIMETICS – GALANTAMINE
≠ galantamine levels Inhibition of CYP3A4-mediated metabolism of galantamine
Be aware; watch for ≠ side-effects from galantamine
ERYTHROMYCIN, CLARITHROMYCIN
PERIPHERAL VASODILATORS – CILOSTAZOL
Cilostazol levels ≠ by erythromycin and possibly clarithromycin
Erythromycin and clarithromycin inhibit CYP3A4-mediated metabolism of cilostazol
Avoid co-administration
MACROLIDES PHOSPHODIESTERASE TYPE 5 INHIBITORS
≠ phosphodiesterase type 5 inhibitor levels with erythromycin, and possibly clarithromycin and telithromycin
Inhibition of metabolism ↓ dose of these phosphodiesterase inhibitors (e.g. start vardenafil at 5 mg)
CLARITHROMYCIN PROTON PUMP INHIBITORS – OMEPRAZOLE
≠ efficacy and adverse effects of both drugs
≠ plasma concentration of both drugs
No dose adjustment recommended. Interaction considered useful for Helicobacter pylori eradication
D R
U G
STO TR
EA TIN
FEC TIO
N S
A N
TIB IO
TIC S-M
A C
R O
LID ES
