chapter
Antibiotics – rifamycins
Pages 9

Monitor analgesic effects; consider using alternative NSAIDs

RIFAMPICIN OPIOIDS ↓ effect of alfentanil, codeine, methadone and morphine

Rifampicin ≠ the hepatic metabolism of these opioids (alfentanil by CYP3A4, codeine by CYP2D6, morphine unknown). Rifampicin is also known to induce intestinal P-gp, which may ↓ bioavailability of oral morphine

Be aware that alfentanil, codeine, methadone and morphine doses may need to be ≠

RIFAMPICIN PARACETAMOL Rifampicin ↓ paracetamol levels Rifampicin ≠ glucuronidation of paracetamol

Warn patients that paracetamol may be less effective

RIFAMYCINS ANTACIDS ↓ rifamycin levels ↓ absorption Separate doses by 2-3 hours RIFAMYCINS ANTIARRHYTHMICS

RIFAMPICIN AMIODARONE ↓ levels of amiodarone Uncertain, but rifampicin is a known enzyme inducer and may therefore ≠ metabolism of amiodarone

Watch for a poor response to amiodarone

RIFAMPICIN DISOPYRAMIDE Disopyramide levels are ↓ by rifampicin

Rifampicin induces hepatic metabolism of disopyramide

Watch for poor response to disopyramide; check serum levels if necessary

RIFAMPICIN MEXILETINE Rifampicin ↓ mexiletine levels Uncertain; postulated that rifampicin may ≠ mexiletine metabolism

Watch for poor response to mexiletine

RIFAMPICIN PROPAFENONE Rifampicin may ↓ propafenone levels

Rifampicin may inhibit CYP3A4/1A2-mediated metabolism of propafenone

Watch for poor response to propafenone

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DRUGS TO TREAT INFECTIONS ANTIBIOTICS – RIFAMYCINS

Rifamycins induce metabolism of dapsone

Watch for poor response to dapsone

RIFAMYCINS MACROLIDES 1. ↓ levels of clarithromycin and telithromycin with rifampicin 2. ≠ rifabutin levels with macrolides

1. Rifampicins induce metabolism of these macrolides 2. Inhibition of CYP3A4-mediated metabolism of rifabutin

1. Watch for poor response to clarithromycin and telithromycin, which may last up to 2 weeks after stopping rifampicin 2. Watch for early features of toxicity of rifabutin; in particular, warn patients to report painful eyes

RIFAMPICIN QUINUPRISTIN/ DALFOPRISTIN

Risk of hepatic toxicity Additive effect Monitor LFTs closely

RIFAMYCINS ANTICANCER AND IMMUNOMODULATING DRUGS

RIFAMPICIN DASATINIB ↓ dasatinib levels Rifampicin ≠ metabolism of dasatinib

Avoid co-administration

RIFAMPICIN ERLOTINIB ↓ erlotinib levels Rifampicin ≠ metabolism of erlotinib

Avoid co-administration

RIFAMPICIN IFOSFAMIDE ≠ rate of biotransformation to 4-hydroxyifosfamide, the active metabolite, but no change in AUC of 4-hydroxyifosfamide

Due to ≠ rate of metabolism and of clearance due to induction of CYP3A4 and CYP2D6

Be aware – clinical significance may be minimal or none

RIFAMPICIN IMATINIB ↓ imatinib levels Due to induction of CYP3A4mediated metabolism of imatinib

Dose adjustments are necessary if concomitant administration is considered absolutely necessary; best, however, to avoid concomitant use

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Mechanism Precautions

efficacy. The effects may last for 3 weeks after discontinuation of CYP-inducer therapy

Due to induction of CYP3A4mediated metabolism of irinotecan

Avoid concomitant use whenever possible; if not, ≠ dose of irinotecan by 50%

RIFAMPICIN PACLITAXEL ↓ plasma concentration of paclitaxel and ↓ efficacy of paclitaxel

Due to induction of hepatic metabolism of paclitaxel by the CYP isoenzymes

Monitor for clinical efficacy, and need to ≠ dose if inadequate response is due to interaction

RIFAMPICIN SUNITINIB ↓ sunitinib levels Rifampicin ≠ metabolism of sunitinib

Avoid co-administration

RIFAMPICIN VINCA ALKALOIDS – VINBLASTINE, VINCRISTINE

↓ of plasma concentrations of vinblastine and vincristine, with risk of inadequate therapeutic response. Reports of ↓ AUC by 40% and elimination half-life by 35%, and ≠ clearance by 63%, in patients with brain tumours taking vincristine, which could lead to dangerously inadequate therapeutic responses

Due to induction of CYP3A4mediated metabolism

Monitor for clinical efficacy and ≠ dose of vinblastine and vincristine as clinically indicated; in the latter case, monitor clinically and radiologically for clinical efficacy in patients with brain tumours and ≠ dose to obtain the desired response

RIFAMPICIN TAMOXIFEN ↓ plasma concentrations of tamoxifen and risk of inadequate therapeutic response

Due to induction of metabolism of tamoxifen by the CYP3A isoenzymes by rifampicin

Avoid concurrent use if possible. Otherwise monitor for clinical efficacy of tamoxifen and ≠ dose of tamoxifen if required

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DRUGS TO TREAT INFECTIONS ANTIBIOTICS – RIFAMYCINS

↓ rejection

drugs. The potency of induction varies

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

RIFAMPICIN CORTICOSTEROIDS ↓ plasma concentrations of corticosteroids and risk of poor or inadequate therapeutic response, which would be undesirable if used for e.g. cerebral oedema

Due to induction of the hepatic metabolism by the CYP3A4 isoenzymes

Monitor therapeutic response closely – clinically, with ophthalmoscopy and radiologically – and ≠ dose of corticosteroids for desired therapeutic effect

RIFAMPICIN MYCOPHENOLATE Significant ↓ plasma mycophenolate concentrations (60% with rifampicin)

Attributed to induction of glucuronyl transferase

Avoid co-administration

RIFAMPICIN SIROLIMUS ↓ sirolimus levels Induction of CYP3A4-mediated metabolism of sirolimus

Avoid co-administration

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

Avoid co-administration

RIFAMPICIN ANTICOAGULANTS – ORAL

↓ anticoagulant effect Rifampicin induces CYP2C9-mediated metabolism of warfarin

Monitor INR closely for at least 1 week after starting rifampicin and up to 5 weeks after stopping it. During co-administration, the warfarin dose may need to be markedly ≠

RIFAMPICIN ANTIDIABETIC DRUGS

RIFAMPICIN PIOGLITAZONE, ROSIGLITAZONE

Significant ↓ blood levels of rosiglitazone. Metabolism and clearance is ≠, the latter threefold

Rosiglitazone is metabolized primarily by CYP2C8 with a minor contribution from CYP2C9. Rifampicin is a potent inducer of CYP2C8 and CYP2C9, and ≠ formation of N-desmethylrosiglitazone by about 40%

May need to use an alternative drug or ≠ dose of rosiglitazone

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↓ AUC of repaglinide by 25%

Due to inducing CYP3A4 isoenzymes that metabolize repaglinide. However, the alternative pathway – CYP2C8 – is unaffected by these inducers except by rifampicin

The interaction is likely to be most severe with rifampicin. Be aware and monitor for hypoglycaemia ➣ For signs and symptoms of hypoglycaemia, see Clinical Features of Some Adverse Drug Interactions, Hypoglycaemia

RIFAMPICIN SULPHONYLUREAS ↓ hypoglycaemic efficacy Plasma levels of sulphonylureas are ↓ by induction of CYPmediated metabolism

RIFAMPICIN ANTIEMETIC

RIFAMPICIN APREPITANT ↓ aprepitant levels Induction of CYP3A4-mediated metabolism of aprepitant

Watch for poor response to aprepitant

RIFAMPICIN 5-HT3 ANTAGONISTS – ONDANSETRON, TROPISETRON

↓ levels of these drugs Induction of metabolism Watch for poor response to ondansetron and tropisetron; consider using an alternative antiemetic

RIFAMYCINS ANTIEPILEPTICS

RIFAMPICIN BARBITURATES ↓ levels of these drugs, with risk of therapeutic failure

Induction of hepatic metabolism Monitor for ↓ clinical efficacy and ≠ their dose as required

RIFABUTIN CARBAMAZEPINE ↓ carbamazepine levels Induction of metabolism Monitor carbamazepine levels RIFAMPICIN LAMOTRIGINE ↓ lamotrigine levels ≠ metabolism Monitor levels RIFAMPICIN, RIFABUTIN PHENYTOIN ↓ phenytoin levels Induced metabolism Monitor phenytoin levels

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DRUGS TO TREAT INFECTIONS ANTIBIOTICS – RIFAMYCINS

POSACONAZOLE, VORICONAZOLE

failure. Rifampicin is a very potent 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. 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 the use of less lipophilic fluconazole, which is less dependent on CYP metabolism. Avoid co-administration of posaconazole with rifabutin

RIFABUTIN VORICONAZOLE ≠ 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 and liver enzymes and examination of eyes for uveitis and corneal opacities is necessary

RIFAMPICIN CASPOFUNGIN ↓ caspofungin levels, with risk of therapeutic failure

Induction of caspofungin metabolism

≠ dose of caspofungin to 70 mg daily

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

RIFAMPICINS ANTIHYPERTENSIVES AND HEART FAILURE DRUGS

RIFAMPICIN ACE INHIBITORS ↓ plasma concentrations and efficacy of imidapril and enalapril

Uncertain. ↓ production of active metabolites has been noted despite rifampicin being an enzyme inducer

Monitor BP at least weekly until stable

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LOSARTAN

Rifampicin induces CYP2C9 Monitor BP at least weekly until stable

RIFAMPICIN VASODILATOR ANTIHYPERTENSIVES

↓ bosentan levels Induction of metabolism Avoid co-administration

RIFAMYCINS ANTIMALARIALS – ATOVAQUONE

Both rifampicin and rifabutin ↓ atovaquone levels, although the effect is greater with rifampicin (↓ AUC 50% cf. with 34% 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

RIFAMPICIN ANTIMIGRAINE DRUGS – ALMOTRIPTAN

Possible ↓ plasma concentrations of almotriptan, with risk of inadequate therapeutic efficacy

One of the major metabolizing enzymes of almotriptan – CYP3A4 isoenzymes – are induced by rifampicin. As there are alternative metabolic pathways, the effect may not be significant and could vary from individual to individual

Be aware of possibility of ↓ response to triptan and consider ≠ dose if the effect is considered to be due to interaction

RIFAMPICIN ANTIPROTOZOALS – LEVAMISOLE

↓ therapeutic efficacy of rifampicin Levamisole displaces rifampicin from protein-binding sites and ≠ free fraction nearly three times and thus ≠ clearance of rifampicin

Avoid co-administration if possible

RIFABUTIN, RIFAMPICIN ANTIPSYCHOTICS – ARIPIPRAZOLE, CLOZAPINE, HALOPERIDOL

↓ levels of these antipsychotics ≠ metabolism Watch for poor response to these antipsychotics; consider ≠ dose

RIFAMYCINS ANTIVIRALS

RIFABUTIN EFAVIRENZ Possible ↓ efficacy of rifabutin ↓ bioavailability ≠ rifabutin dose by 50% for daily treatment, or double the dose if the patient is on treatment two or three times a week

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DRUGS TO TREAT INFECTIONS ANTIBIOTICS – RIFAMYCINS

Inhibition of CYP3A4-mediated metabolism. Nelfinavir also competitively inhibits 2C19

↓ rifabutin dose by at least 50% when given with amprenavir, indinavir or nelfinavir, and by 75% with atazanavir, ritonavir (with or without lopinavir) or tipranavir

RIFABUTIN SAQUINAVIR ↓ efficacy of saquinavir Uncertain; probably via altered CYP3A4 metabolism

Avoid co-administration

RIFAMPICIN EFAVIRENZ Possible ↓ efficacy of efavirenz Uncertain ≠ dose of efavirenz from 600 mg to 800 mg

RIFAMPICIN NEVIRAPINE ↓ efficacy of nevirapine Uncertain; probable ≠ metabolism of nevirapine

Avoid concomitant use. FDA recommend use only if clearly indicated and monitored closely

RIFAMPICIN PROTEASE INHIBITORS ↓ levels of protease inhibitor. Risk of hepatotoxicity with saquinavir

Induction of metabolism Avoid co-administration

RIFAMPICIN ZIDOVUDINE Unclear Unclear Avoid co-administration

RIFAMYCINS ANXIOLYTICS AND HYPNOTICS

RIFAMPICIN BZDs, NOT LORAZEPAM, OXAZEPAM, TEMAZEPAM

↓ BZD levels Induction of CYP3A4-mediated metabolism

Watch for poor response to these BZDs; consider ≠ dose, e.g. diazepam or nitrazepam 2-3-fold

RIFAMPICIN BUSPIRONE ↓ buspirone levels Induction of CYP3A4-mediated metabolism

Watch for poor response to buspirone; consider ≠ dose

RIFAMPICIN ZALEPLON, ZOLPIDEM, ZOPICLONE

↓ levels of these hypnotics Induction of CYP3A4-mediated metabolism

Watch for poor response to these agents

RIFAMPICIN BETA-BLOCKERS ↓ plasma concentrations and efficacy of bisoprolol, carvedilol, celiprolol, metoprolol and propanolol

Rifampicin induces hepatic enzymes (e.g. CYP2C19), which ≠ metabolism of the betablockers; in addition, it may also ≠ P-gp expression

Monitor PR and BP; watch for poor response to beta-blockers

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failure

Due to induction of CYP1A2 and CYP3A3

May need to ≠ dose of theophylline by 25%

RIFAMPICIN CALCIUM CHANNEL BLOCKERS

Plasma concentrations of calcium channel blockers may be ↓ by rifampicin

Rifampicin induces CYP3A4mediated metabolism of calcium channel blockers. It also induces CYP2C9-mediated metabolism of verapamil and induces intestinal P-gp, which may ↓ bioavailability of verapamil

Monitor BP closely; watch for ↓ effect of calcium channel blockers

RIFAMYCINS CARDIAC GLYCOSIDES

RIFAMPICIN DIGOXIN Plasma concentrations of digoxin may be ↓ by rifampicin

Rifampicin seems to induce P-gpmediated excretion of digoxin in the kidneys

Watch for ↓ response to digoxin, check plasma levels and ≠ dose as necessary

RIFAMPICIN DIGITOXIN Plasma concentrations of digitoxin may be halved by rifampicin

Due to ≠ hepatic metabolism Watch for poor response to digitoxin

RIFAMPICIN, RIFABUTIN CNS STIMULANTS – MODAFINIL

↓ plasma concentrations of modafinil, with possibility of ↓ therapeutic effect

Induction of CYP3A4, which has a partial role in the metabolism of modafinil

Be aware

RIFAMPICIN DIURETICS – POTASSIUMSPARING

↓ eplerenone levels Induction of metabolism Avoid co-administration

RIFAMPICIN DRUG DEPENDENCE THERAPIES – BUPROPION

↓ plasma concentrations of bupropion and lack of therapeutic effect

Induction of CYP2B6 ≠ dose of bupropion cautiously

RIFAMPICIN GESTRINONE ↓ gestrinone levels Induction of metabolism Watch for poor response to gestrinone

RIFAMPICIN H2 RECEPTOR BLOCKERS – CIMETIDINE

↓ efficacy of cimetidine ≠ metabolism Change to alternative acid suppression, e.g. rabeprazole, or ≠ dose and/or frequency