ABSTRACT
Monitor closely for opioid withdrawal, ≠ dose as necessary. Likely to need dose titration of methadone (mean 22% but up to 186% ≠)
NNRTIs ANTIBIOTICS
NNRTIs MACROLIDES – CLARITHROMYCIN
1. ↓ efficacy of clarithromycin but ≠ efficacy and adverse effects of active metabolite 2. 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
EFAVIRENZ RIFABUTIN Possible ↓ efficacy of rifabutin ↓ bioavailability ≠ rifabutin dose by 50% for daily treatment, or double the dose if patient is on two or three times a week treatment
EFAVIRENZ RIFAMPICIN Possible ↓ efficacy of efavirenz Uncertain ≠ dose of efavirenz from 600 mg to 800 mg
NEVIRAPINE RIFAMPICIN ↓ efficacy of nevirapine Uncertain; probable ≠ metabolism of nevirapine
Avoid concomitant use. FDA recommend use only if clearly indicated and monitored closely
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DRUGS TO TREAT INFECTIONS ANTIVIRALS – ANTIRETROVIRALS Non-nucleoside reverse transcriptase inhibitors
EFAVIRENZ DOXORUBICIN ≠ risk of myelosuppression due to ≠ plasma concentrations
Due to ↓ metabolism of doxorubicin by CYP3A4 isoenzymes owing to inhibition of those enzymes
Monitor for ≠ myelosuppression, peripheral neuropathy, myalgias and fatigue
EFAVIRENZ 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
EFAVIRENZ 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 and signs of oedema (including pulmonary oedema). Monitor electrolytes, liver function and for cardiotoxicity
EFAVIRENZ 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 efavirenz
Peripheral blood counts should be checked before each course of treatment. Monitor lung function. Recommendation is to ↓ dose of irinotecan by 25%
EFAVIRENZ VINCA ALKALOIDS ≠ 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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Mechanism Precautions
toremifene
Due to inhibition of metabolism of toremifene by the CYP3A4 isoenzymes by efavirenz
Clinical relevance is uncertain. Necessary to monitor for clinical toxicities
NNRTIs CICLOSPORIN ↓ efficacy of ciclosporin Possibly ≠ CYP3A4-mediated metabolism of ciclosporin
Monitor more closely; check levels
EFAVIRENZ 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
NEVIRAPINE ANTICOAGULANTS – WARFARIN
↓ efficacy of warfarin with nevirapine
Altered metabolism. S-warfarin is metabolized by CYP2D6, Rwarfarin by CYP3A4
Monitor INR every 3-7 days when starting or altering treatment and adjust dose by 10% as necessary. May need around twofold ≠ in dose
EFAVIRENZ ANTIDEPRESSANTS – SSRIs 1. Possible ≠ efficacy and ≠ adverse effects, including serotonin syndrome, with fluoxetine 2. Possible ↓ efficacy with sertraline
1. Uncertain mechanism; possibly ≠ bioavailability 2. CYP2B6 contributes most to the demethylation of sertraline with lesser contributions from CYP2C19, CYP2C9, CYP3A4 and CYP2D6
1. Use with caution; consider ↓ dose of fluoxetine 2. Watch for therapeutic failure, and advise patients to report persistence or lack of improvement of symptoms of depression. ≠ dose of sertraline as required, titrating to clinical response
EFAVIRENZ ANTIDIABETIC DRUGS – REPAGLINIDE
Likely to ≠ plasma concentrations of repaglinide and ≠ risk of hypoglycaemic episodes
Due to inhibition of CYP3A4 isoenzymes, which metabolize repaglinide
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DRUGS TO TREAT INFECTIONS ANTIVIRALS – ANTIRETROVIRALS Non-nucleoside reverse transcriptase inhibitors
Uncertain Monitor carbamazepine levels and side-effects when initiating or changing treatment
NNRTIs ANTIFUNGALS
NNRTIs AZOLES – KETOCONAZOLE, VORICONAZOLE
Possible ↓ efficacy of azole ≠ CYP3A4-mediated metabolism Avoid co-administration
EFAVIRENZ, NEVIRAPINE CASPOFUNGIN ↓ caspofungin levels, with risk of therapeutic failure
Induction of caspofungin metabolism
≠ dose of caspofungin to 70 mg daily
NNRTIs ANTIGOUT DRUGS – PROBENECID
≠ levels of zidovudine with cases of toxicity
↓ hepatic metabolism of zidovudine
Avoid co-administration if possible; if not possible, ↓ dose of zidovudine
NNRTIs ANTIMIGRAINE DRUGS
NNRTIs ERGOT DERIVATIVES ≠ ergotamine/methysergide levels, with risk of toxicity
↓ CYP3A4-mediated metabolism of ergot derivatives
Avoid co-administration
EFAVIRENZ 5-HT1 AGONISTSALMOTRIPTAN, ELETRIPTAN
≠ plasma concentrations of almotriptan and eletriptan, and risk of toxic effects, e.g. flushing, sensations of tingling, heat, heaviness, pressure or tightness of any part of body including the throat and chest, dizziness
Almotriptan and eletriptan are metabolized by CYP3A4 isoenzymes, which may be inhibited by efavirenz. However, since there is an alternative pathway of metabolism by MAOA, the toxicity responses will vary between individuals
The CSM has advised that if chest tightness or pressure is intense, the triptan should be discontinued immediately and the patient investigated for ischaemic heart disease by measuring cardiac enzymes and doing an ECG. Avoid concomitant use in patients with coronary artery disease and in those with severe or uncontrolled hypertension
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Mechanism Precautions
≠ CYP3A4-mediated metabolism of aripiprazole
Monitor patient closely and ≠ dose of aripiprazole as necessary
NNRTIs PIMOZIDE Possible ≠ efficacy and ≠ adverse effects, e.g. ventricular arrhythmias of pimozide
↓ CYP-3A4-mediated metabolism of pimozide
Avoid co-administration
NNRTIs ANTIVIRALS
EFAVIRENZ NNRTIs-NEVIRAPINE ↓ efficacy of efavirenz when co-administered with nevirapine
Uncertain mechanism: ↓ bioavailability
If co-administered, consider ≠ dose of efavirenz to 800 mg once daily
EFAVIRENZ NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS – DIDANOSINE (ENTERIC-COATED), TENOFOVIR
A high treatment failure rate is reported when tenofovir, entericcoated didanosine and efavirenz are co-administered
Unknown Use this combination with caution
NNRTIs INDINAVIR Possible ↓ efficacy of indinavir ≠ CYP3A4-mediated metabolism of indinavir
Monitor viral load; consider ≠ dose indinavir to 1000 mg 8-hourly
NNRTIs LOPINAVIR AND RITONAVIR
Possible ↓ efficacy of lopinavir/ritonavir
Uncertain; ↓ bioavailability Consider ≠ lopinavir/ritonavir dose (by 33% with efavirenz and to 53 mg/133 mg twice daily, and monitor drug concentrations, with nevirapine). Monitor viral load closely as this dose ≠ may be insufficient. Monitor LFTs closely
EFAVIRENZ AMPRENAVIR Possible ↓ efficacy of amprenavir Uncertain; ↓ bioavailability of amprenavir
Consider ≠ dose of amprenavir to 1200 mg three times a day, or combine amprenavir 600 mg twice a day with ritonavir 100 mg twice a day
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DRUGS TO TREAT INFECTIONS ANTIVIRALS – ANTIRETROVIRALS Non-nucleoside reverse transcriptase inhibitors
≠ CYP3A4-mediated metabolism of efavirenz
Recommended dose of atazanavir is 400 mg when given with efavirenz 600 mg. Optimal suggested treatment is this combination plus ritonavir 100 mg daily
EFAVIRENZ NELFINAVIR Possible ≠ efficacy of nelfinavir, with theoretical risk of adverse effects
Small ≠ bioavailability of nelfinavir No dose adjustment necessary
EFAVIRENZ RITONAVIR ≠ efficacy and ≠ adverse effects of ritonavir, e.g. dizziness, nausea, paraesthesia and liver dysfunction
≠ bioavailability of ritonavir; competition for metabolism via CYP3A4
Combination not well tolerated. Monitor closely including LFTs. Lowdose ritonavir has not been studied
EFAVIRENZ SAQUINAVIR Possible ↓ efficacy of saquinavir, with risk of treatment failure
≠ CYP3A4-mediated metabolism of saquinavir
Combination not recommended if saquinavir is the sole protease inhibitor; always use saquinavir in combination with another agent, e.g. ritonavir, when co-administering with efavirenz
NEVIRAPINE AMPRENAVIR Efficacy of amprenavir predicted to be ↓
Uncertain; ↓ bioavailability of amprenavir
Monitor viral load
NEVIRAPINE ATAZANAVIR ↓ efficacy of atazanavir Atazanavir is a substrate and inhibitor of CYP3A4
Avoid concomitant use
NEVIRAPINE NELFINAVIR Possible ↓ efficacy of nelfinavir Uncertain Dose adjustment probably not required, although one study suggests ≠ dose may be required
NEVIRAPINE SAQUINAVIR Possible ↓ efficacy, risk of treatment failure of saquinavir
≠ CYP3A4-mediated metabolism of saquinavir
Clinical significance unclear. Different formulations of saquinavir may have different magnitudes of interaction
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Mechanism Precautions
MIDAZOLAM
↓ CYP3A4-mediated metabolism of diazepam and midazolam
With all anxiolytics, monitor more closely, especially sedation levels. May need ↓ dose of diazepam or alteration of timing of dose. Avoid co-administration with midazolam
EFAVIRENZ, NEVIRAPINE CNS STIMULANTS – MODAFINIL
May ↓ modafinil levels Induction of CYP3A4, which has a partial role in the metabolism of modafinil
Be aware
EFAVIRENZ DRUG DEPENDENCE THERAPIES – BUPROPION
≠ plasma concentrations of bupropion and risk of adverse effects
Inhibition of CYP2B6 Warn patients about adverse effects, and use alternatives when possible. Co-administer efavirenz and bupropion with caution. A retrospective study showed that two patients received the combination without reported adverse effects. Potential ≠ risk of seizures
EFAVIRENZ GRAPEFRUIT JUICE Possibly ≠ efficacy and ≠ adverse effects
Unclear Monitor more closely
EFAVIRENZ LIPID-LOWERING DRUGS – STATINS
↓ levels of atorvastatin, pravastatin and simvastatin with efavirenz
Uncertain; efavirenz is known to induce intestinal P-gp, which may ↓ bioavailability of some statins (including atorvastatin)
Monitor lipid profile closely
NEVIRAPINE OESTROGENS – ETHINYLESTRADIOL
Marked ↓ contraceptive effect with nevirapine
Induction of metabolism of oestrogens
Avoid co-administration, recommend alternative non-hormonal contraceptives – barrier methods are necessary to prevent transmission of infection
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DRUGS TO TREAT INFECTIONS ANTIVIRALS – ANTIRETROVIRALS Nucleoside reverse transcriptase inhibitors
Uncertain Avoid co-administration; recommend alternative non-hormonal contraceptives – barrier methods are necessary to prevent transmission of infection
NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
ANALGESICS
ZIDOVUDINE NSAIDs Risk of haematological effects of zidovudine with NSAIDs
Unknown Avoid co-administration
ABACAVIR OPIOIDS ↓ efficacy of methadone when co-administered with abacavir
Uncertain; possibly enzyme induction
Monitor for opioid withdrawal and consider ≠ dose
DIDANOSINE, ZIDOVUDINE
PARACETAMOL Cases of hepatotoxicity reported when paracetamol was added to either didanosine or zidovudine
Uncertain; possible additive hepatotoxic effect
Monitor liver function regularly during co-administration
NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
ANTIBIOTICS
NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
AMINOGLYCOSIDES Possibly ≠ risk of nephrotoxicity Additive effect Avoid co-administration if possible; otherwise monitor renal function weekly
DIDANOSINE ETHAMBUTOL Possibly ≠ adverse effects (e.g. peripheral neuropathy) with didanosine
Additive side-effects Monitor closely for development of peripheral neuropathy, but no dose adjustment required
STAVUDINE, ZIDOVUDINE CHLORAMPHENICOL Possible ≠ adverse effects when co-administered with stavudine or zidovudine
Uncertain Use an alternative antibiotic, if possible; otherwise monitor closely for peripheral neuropathy and check FBC regularly
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Mechanism Precautions INHIBITORS
Additive toxicity ↓ doses as necessary; monitor FBC and renal function closely. Doses of co-trimoxazole used for prophylaxis seem to be tolerated
ZIDOVUDINE DAPSONE Possible ≠ adverse effects when co-administered with zidovudine
Uncertain; possible ≠ bioavailability of zidovudine
Use with caution, monitor for peripheral neuropathy
NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
ISONIAZID ≠ adverse effects with didanosine and possibly stavudine
Additive side-effects Monitor closely for the development of peripheral neuropathy, but no dose adjustment required
DIDANOSINE, STAVUDINE METRONIDAZOLE ≠ adverse effects (e.g. peripheral neuropathy) with didanosine and possibly stavudine
Additive effect Monitor closely for peripheral neuropathy during intensive or prolonged combination
ZIDOVUDINE RIFAMPICIN Unclear Unclear Avoid co-administration
DIDANOSINE QUINOLONES ↓ efficacy of ciprofloxacin and possibly levofloxacin, moxifloxacin, norfloxacin and ofloxacin with buffered didanosine
Cations in the buffer of didanosine preparation chelate and adsorb ciprofloxacin. Absorption of the other quinolones may be ↓ by the buffered didanosine formulation, which raises gastric pH
Give the antibiotic 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
DIDANOSINE TETRACYCLINES ↓ efficacy of tetracycline, and possibly demeclocycline, doxycycline, lymecycline, minocycline and oxytetracycline with buffered didanosine
Absorption may be affected by the buffered didanosine formulation, which ≠ gastric pH
Avoid co-administration with buffered didanosine preparations. Consider changing to enteric-coated didanosine tablets
NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
TRIMETHOPRIM Possibly ≠ haematological toxicity Competition for renal excretion Monitor FBC and renal function closely
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DRUGS TO TREAT INFECTIONS ANTIVIRALS – ANTIRETROVIRALS Nucleoside reverse transcriptase inhibitors
Additive toxicity Monitor FBC and renal function closely (at least weekly)
TRANSCRIPTASE INHIBITORS
ZIDOVUDINE DOXORUBICIN ≠ adverse effects when doxorubicin is co-administered with zidovudine
Additive toxicity Monitor FBC and renal function closely. ↓ doses as necessary
DIDANOSINE, ZIDOVUDINE
HYDROXYCARBAMIDE ≠ adverse effects with didanosine and possibly zidovudine
Additive effects, enhanced antiretroviral activity via ↓ intracellular deoxynucleotides
Avoid co-administration
ZIDOVUDINE VINCA ALKALOIDS ≠ adverse effects when vincristine and possibly vinblastine are co-administered with zidovudine
Additive toxicity Use with caution. Monitor FBC and renal function closely. ↓ doses as necessary
LAMIVUDINE AZATHIOPRINE ≠ adverse effects with lamivudine Unclear Monitor closely TENOFOVIR IL-2 ≠ adverse effects with tenofovir Uncertain Avoid if possible, otherwise monitor
renal function weekly
ZIDOVUDINE INTERFERON ≠ adverse effects with zidovudine Additive toxicity Monitor FBC and renal function closely. ↓ doses as necessary. Use of pyrimethamine as prophylaxis seems to be tolerated
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Mechanism Precautions INHIBITORS
DIDANOSINE, STAVUDINE, ZIDOVUDINE
PHENYTOIN Possibly ≠ adverse effects (e.g. peripheral neuropathy) with didanosine, stavudine and zidovudine
Additive effect Monitor closely for peripheral neuropathy during prolonged combination
ZIDOVUDINE VALPROATE ≠ zidovudine levels Inhibition of metabolism Watch for early features of toxicity of zidovudine
NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
ANTIFUNGALS
TENOFOVIR, ZIDOVUDINE AMPHOTERICIN Possibly ≠ adverse effects with tenofovir and zidovudine
Additive toxicity Avoid if possible, otherwise monitor FBC and renal function (weekly). ↓ doses as necessary
ZIDOVUDINE AZOLES – FLUCONAZOLE ≠ zidovudine levels Inhibition of metabolism Avoid co-administration DIDANOSINE AZOLES – ITRACONAZOLE,
KETOCONAZOLE Possibly ↓ efficacy of ketoconazole and itraconazole with buffered didanosine
Absorption of 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
ZIDOVUDINE FLUCYTOSINE Possibly ≠ adverse effects with zidovudine
Additive toxicity Avoid if possible; otherwise monitor FBC and renal function (weekly). ↓ doses as necessary
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DRUGS TO TREAT INFECTIONS ANTIVIRALS – ANTIRETROVIRALS Nucleoside reverse transcriptase inhibitors
DIDANOSINE ALLOPURINOL Didanosine levels may be ≠ Uncertain Watch for early signs of toxicity ZIDOVUDINE PROBENECID ≠ levels of zidovudine, with cases
of toxicity ↓ hepatic metabolism of zidovudine
Avoid co-administration if possible; if not possible, ↓ dose of zidovudine
NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
ANTIHYPERTENSIVES AND HEART FAILURE DRUGS – VASODILATOR ANTIHYPERTENSIVES
Risk of peripheral neuropathy when hydralazine is co-administered with didanosine, stavudine or zalcitabine
Additive effect; both drugs can cause peripheral neuropathy
Warn patients to report early features of peripheral neuropathy; if this occurs, the nucleoside reverse transcriptase inhibitor should be stopped
NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
ANTIMALARIALS
ZIDOVUDINE ATOVAQUONE Atovaquone ≠ zidovudine levels Atovaquone inhibits glucuronidation of zidovudine
Uncertain clinical significance. Monitor FBC, LFTs and lactate closely during co-administration
ZIDOVUDINE PYRIMETHAMINE 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
NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
ANTIPROTOZOALS – PENTAMIDINE ISETIONATE
≠ adverse effects with didanosine, tenofovir and zidovudine
Additive toxicity Monitor FBC and renal function closely. Consider stopping didanosine while pentamidine is required for Pneumocystis jiroveci pneumonia
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Mechanism Precautions INHIBITORS
TENOFOVIR ADEFOVIR, CIDOFOVIR ≠ adverse effects ≠ plasma levels, competition for renal excretion via organic anion transporter
Monitor renal function weekly
LAMIVUDINE, TENOFOVIR, ZALCITABINE
FOSCARNET SODIUM ≠ adverse effects with tenofovir and possibly lamivudine and zalcitabine
Uncertain; possibly additive toxicity via competition for renal excretion
Avoid if possible; otherwise monitor FBC and renal function weekly
NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
GANCICLOVIR/VALGANCIC LOVIR
1. ≠ adverse effects with tenofovir, zidovudine and possibly didanosine, lamivudine and zalcitabine 2. Possibly ↓ efficacy of ganciclovir
1. Uncertain; possibly additive toxicity. Lamivudine may compete for active tubular secretion in the kidneys 2. Uncertain; ↓ bioavailability
1. Avoid if possible; otherwise monitor FBC and renal function weekly. It has been suggested that the dose of zidovudine should be halved from 600 mg to 300 mg daily. Monitor for peripheral neuropathy, particularly with zalcitabine 2. Uncertain clinical significance; if in doubt, consider alternative cytomegalovirus prophylaxis
NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
RIBAVIRIN 1. ≠ side-effects, risk of lactic acidosis, peripheral neuropathy, pancreatitis, hepatic decompensation, mitochondrial toxicity and anaemia with didanosine and stavudine 2. ↓ efficacy of lamivudine
1. Additive side-effects; ≠ intracellular activation of didanosine and stavudine 2. ↓ intracellular activation of lamivudine
1. Not recommended. Use with extreme caution; monitor lactate, LFTs and amylase closely. Stop co-administration if peripheral neuropathy occurs. Stavudine and didanosine carry a higher risk 2. Monitor HIV RNA levels; if they ≠, review treatment combination
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DRUGS TO TREAT INFECTIONS ANTIVIRALS – ANTIRETROVIRALS Nucleoside reverse transcriptase inhibitors
COATED), TENOFOVIR
reported when tenofovir, entericcoated didanosine and efavirenz are co-administered
Unknown Use this combination with caution
EMTRICITABINE LAMIVUDINE Unknown Unknown Combination not recommended. No clinical experience of co-administration
DIDANOSINE STAVUDINE ≠ adverse effects, including pancreatitis and neuropathy
Additive effect Monitor more closely, especially for pancreatitis and peripheral neuropathy. Relative risk of neuropathy: stavudine alone 1.39 compared with didanosine; combined use 3.5. Sometimes fatal lactic acidosis is reported in pregnancy
DIDANOSINE TENOFOVIR Possibly ≠ adverse effects, including pancreatitis, lactic acidosis and neuropathy
≠ plasma levels of didanosine additive effects
Co-administration not recommended. Monitor closely for antiviral efficacy and side-effects (pancreatitis, neuropathy, lactic acidosis, renal failure). Not recommended in patients with a high viral load and low CD4 count (enteric-coated and buffered tablets). ↓ dose of didanosine to 250 mg has been tried. Do not use in combination as triple therapy with lamivudine as there is a high level of treatment failure
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Mechanism Precautions Uncertain Monitor more closely, especially for
haematological toxicity
EMTRICITABINE ZIDOVUDINE Possibly ≠ adverse effects ≠ bioavailability of zidovudine Watch for adverse effects of zidovudine
LAMIVUDINE ZIDOVUDINE Possibly ≠ adverse effects Additive side-effects Monitor closely, especially for blood dyscrasias. Check FBC prior to concomitant use and then every month for 3 months
STAVUDINE ZIDOVUDINE Possibly ↓ efficacy ↓ cellular activation of stavudine and antagonism in vivo. Both are phosphorylated to the active form by thymidine kinase, which preferentially phosphorylates zidovudine; therefore causes ↓ phosphorylation of stavudine
Avoid co-administration
TENOFOVIR ATAZANAVIR ↓ efficacy of atazanavir Uncertain; ↓ plasma levels of atazanavir
Use with caution, and consider using in combination with ritonavir
STAVUDINE NELFINAVIR Possibly ≠ adverse effects Uncertain Warn patient that diarrhoea may occur ZIDOVUDINE LOPINAVIR RITONAVIR ↓ efficacy of zidovudine ↓ plasma levels by ≠ glucu-
ronidation Avoid co-administration
DIDANOSINE (BUFFERED) PROTEASE INHIBITORS ↓ efficacy of amprenavir, atazanavir and indinavir
Absorption of these protease inhibitors may be affected by the buffered didanosine formulation, which ≠ gastric pH
Separate doses by at least 1 hour. Alternatively, consider using the enteric-coated formulation of didanosine
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DRUGS TO TREAT INFECTIONS ANTIVIRALS – ANTIRETROVIRALS Protease inhibitors
↓
↓ plasma concentrations Not recommended unless there are no other available nucleoside reverse transcriptase inhibitors
COATED)
↓ ↓ absorption Separate doses by at least 2 hours
ZIDOVUDINE TIPRANAVIR RITONAVIR Possible ↓ efficacy; risk of treatment failure of zidovudine
↓ plasma concentrations Not recommended unless there are no other available nucleoside reverse transcriptase inhibitors
ZIDOVUDINE ANXIOLYTICS AND HYPNOTICS – BZDs
≠ adverse effects, including ≠ incidence of headaches when oxazepam is co-administered with zidovudine
Uncertain Monitor closely
ZALCITABINE H2 RECEPTOR BLOCKERS – CIMETIDINE
≠ efficacy and adverse effects of zalcitabine
↓ excretion via inhibition of tubular secretion
Clinical significance unclear. Monitor more closely
PROTEASE INHIBITORS
PROTEASE INHIBITORS ANAESTHETICS – LOCAL ≠ adverse effects of lidocaine with lopinavir and ritonavir
Uncertain; ≠ bioavailability Caution; consider using an alternative local anaesthetic
PROTEASE INHIBITORS ANALGESICS
PROTEASE INHIBITORS NSAIDs – PIROXICAM Ritonavir ≠ piroxicam levels Uncertain; ritonavir is known to inhibit CYP2C9, for which NSAIDs are substrates
Avoid co-administration
PROTEASE INHIBITORS ALFENTANIL, BUPRENORPHINE, FENTANYL, TRAMADOL
Possibly ≠ adverse effects when buprenorphine is co-administered with indinavir, ritonavir (with or without lopinavir) or saquinavir
Inhibition of CYP3A4 (CYP2D6 in the case of tramadol)
Halve the starting dose and titrate to effect. For fentanyl, give a single injection – monitor sedation and respiratory function closely. If continued use of fentanyl is needed, ↓ dose may be required. Concomitant use of ritonavir and transdermal fentanyl is not recommended
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Mechanism Precautions
ritonavir
Inhibition of CYP2D6-mediated metabolism of codeine to its active metabolites
Use an alternative opioid
PROTEASE INHIBITORS METHADONE, PETHIDINE ↓ efficacy of methadone, with risk of withdrawal, when co-administered with amprenavir, nelfinavir, ritonavir (with or without lopinavir) or saquinavir
Uncertain; possibly due to induction of CYP3A4 and CYP2D6
Monitor closely for opioid withdrawal, and ≠ dose of methadone as necessary, This advice includes co-administration of methadone with low-dose ritonavir. Short-term use of pethidine is unlikely to cause a problem
PROTEASE INHIBITORS ANTIARRHYTHMICS
PROTEASE INHIBITORS AMIODARONE Amiodarone levels may be ≠ by protease inhibitors
Uncertain but postulated to be due to ↓ metabolism of amiodarone
Watch closely for amiodarone toxicity; for patients taking high doses of amiodarone, consider ↓ dose when starting protease inhibitor anti-HIV therapy
PROTEASE INHIBITORS DISOPYRAMIDE Disopyramide levels may be ≠ by protease inhibitors
Inhibition of CYP3A4-mediated metabolism of disopyramide
Watch closely for disopyramide toxicity
PROTEASE INHIBITORS FLECAINIDE Amprenavir, ritonavir and possibly saquinavir and tipranavir with ritonavir ≠ flecainide levels, with risk of ventricular arrhythmias
Uncertain; possibly inhibition of CYP3A4-and CYP2D6-mediated metabolism of flecainide
Manufacturers recommend avoiding co-administration of flecainide with amprenavir, ritonavir or saquinavir
PROTEASE INHIBITORS MEXILETINE Mexiletine levels may be ≠ by ritonavir
Inhibition of metabolism via CYP2D6, particularly in rapid metabolizers (90% of the population)
Monitor PR, BP and ECG closely
PROTEASE INHIBITORS PROPAFENONE Amprenavir, ritonavir and possibly saquinavir and tipranavir with ritonavir ≠ propafenone levels, with risk of ventricular arrhythmias
Uncertain Manufacturers recommend avoiding co-administration of propafenone with amprenavir, ritonavir or tipranavir
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DRUGS TO TREAT INFECTIONS ANTIVIRALS – ANTIRETROVIRALS Protease inhibitors
Inhibition of CYP3A4-mediated metabolism of fusidic acid
Avoid co-administration
PROTEASE INHIBITORS MACROLIDES – AZITHROMYCIN
Risk of ≠ adverse effects of azithromycin with nelfinavir
Possibly involves altered P-gp transport
Watch for signs of azithromycin toxicity
PROTEASE INHIBITORS MACROLIDES – CLARITHROMYCIN, ERYTHROMYCIN
Possibly ≠ adverse effects of macrolide with atazanavir, ritonavir (with or without lopinavir) or 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 Mycobacterium avium intracellulare infection; if combined, ↓ dose by 50% (75% in the presence of renal failure with a creatinine clearance of 30 mL/min)
PROTEASE INHIBITORS METRONIDAZOLE ≠ adverse effects, e.g. a disulfiramlike reaction and flushing, with ritonavir (with or without lopinavir)
Ritonavir and lopinavir oral solutions contain alcohol
Warn patients, and give alternative preparations if possible
PROTEASE INHIBITORS RIFABUTIN ≠ efficacy and ≠ adverse effects of rifabutin
Inhibition of CYP3A4-mediated metabolism. Nelfinavir also competitively inhibits CYP2C19
↓ 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
SAQUINAVIR RIFABUTIN ↓ efficacy of saquinavir Uncertain; probably via altered CYP3A4 metabolism
Avoid co-administration
PROTEASE INHIBITORS RIFAMPICIN ↓ levels of the protease inhibitor. Risk of hepatotoxicity with saquinavir
Induction of metabolism Avoid co-administration
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Mechanism Precautions
RITONAVIR IFOSFAMIDE ↓ plasma concentrations of 4hydroxyifosfamide, 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
RITONAVIR 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 and signs of oedema (including pulmonary oedema). Monitor electrolytes, liver function and for cardiotoxicity
RITONAVIR 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 ritonavir
Peripheral blood counts should be checked before each course of treatment. Monitor lung function. Recommendation is to ↓ dose of irinotecan by 25%
PROTEASE INHIBITORS VINCA ALKALOIDS ≠ adverse effects of vinblastine and vincristine
Inhibition of CYP3A4-mediated metabolism 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
RITONAVIR TOREMIFENE ≠ plasma concentrations of toremifene
Due to inhibition of metabolism of toremifene by the CYP3A4 isoenzymes by ritonavir
Clinical relevance is uncertain. Necessary to monitor for clinical toxicities
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DRUGS TO TREAT INFECTIONS ANTIVIRALS – ANTIRETROVIRALS Protease inhibitors
Inhibition of CYP3A4-mediated metabolism of these immunomodulating drugs
Monitor clinical effects closely and check levels
PROTEASE INHIBITORS CORTICOSTEROIDS ≠ plasma levels of betamethasone, dexamethasone, hydrocortisone, prednisolone and both inhaled and intranasal budesonide and fluticasone with ritonavir (with or without lopinavir)
Inhibition of CYP3A4-mediated metabolism
Monitor closely for signs of corticosteroid toxicity and immunosupression, and ↓ dose as necessary. Consider using inhaled beclometasone
PROTEASE INHIBITORS DOCETAXEL, PACLITAXEL ≠ risk of adverse effects of docetaxel and paclitaxel
Inhibition of CYP3A4-mediated metabolism. Also inhibition of P-gp efflux of vinblastine
Use with caution. Additional monitoring is required. Monitor FBC weekly
PROTEASE INHIBITORS DOXORUBICIN ≠ risk of myelosuppression due to ≠ plasma concentrations
Due to ↓ metabolism of doxorubicin by CYP3A4 isoenzymes owing to inhibition of those enzymes
Monitor for ≠ myelosuppression, peripheral neuropathy, myalgias and fatigue
PROTEASE INHIBITORS IL-2 ≠ protease inhibitor levels, with risk of toxicity
Aldesleukin induces the formation of IL-6, which inhibits the metabolism of protease inhibitors by the CYP3A4 isoenzymes
Warn patients to report symptoms such as nausea, vomiting , flatulence, dizziness and rashes. Monitor blood sugar on initiating and discontinuing treatment
PROTEASE INHIBITORS ANTICOAGULANTS – ORAL 1. Anticoagulant effect may be altered (cases of both ≠ and ↓) when ritonavir and possibly saquinavir are given with warfarin 2. Possibly ↓ anticoagulant effect when ritonavir and nelfinavir are given with acenocoumarol
Uncertain. Ritonavir inhibits CYP3A4 and CYP2C9 while inducing CYP1A2
Monitor INR closely
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Mechanism Precautions
paroxetine and sertraline when co-administered with ritonavir (with or without lopinavir). Cardiac and neurological events have been reported, including serotonin syndrome
Ritonavir is associated with the most significant interaction of the protease inhibitors due to potent inhibition of CYP3A, CYP2D6, CYP2C9 and CYP2C19 isoenzymes
Warn patients to watch for ≠ sideeffects of SSRIs and consider ↓ dose of SSRI
PROTEASE INHIBITORS AMITRIPTYLINE ≠ adverse effects when amitriptyline is co-administered with ritonavir (with or without lopinavir), and possibly atazanavir
Inhibition of CYP3A4-mediated metabolism. Note that SSRIs are metabolized by a number of enzymes, including CYP2C9, CYP2C19, CYP2D6 and CYP3A4; therefore, the effect of protease inhibitors is variable
Monitor closely
PROTEASE INHIBITORS AMOXAPINE, CLOMIPRAMINE, DOXEPIN, IMIPRAMINE, NORTRIPTYLINE, TRIMIPRAMINE
Possibly ≠ adverse effects of amoxapine with atazanavir and ritonavir
Inhibition of CYP3A4-mediated metabolism of amoxapine, clomipramine and doxepin; inhibition of CYP3A4-, CYP2D6and CYP2C9-mediated metabolism of imipramine; inhibition of CYP2D6-mediated metabolism of nortriptyline and trimipramine
Monitor closely
PROTEASE INHIBITORS ST JOHN’S WORT Markedly ↓ levels and efficacy of protease inhibitors by St John’s wort
Possibly ≠ CYP3A4-mediated metabolism of protease inhibitors
Avoid co-administration
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DRUGS TO TREAT INFECTIONS ANTIVIRALS – ANTIRETROVIRALS Protease inhibitors
Several mechanisms considered include insulin resistance, impaired insulin-stimulated glucose uptake by skeletal muscle cells, ↓ insulin binding to receptors and inhibition of intrinsic transport activity of glucose transporters in the body
Necessary to establish baseline values for blood sugar before initiating therapy with a protease inhibitor. Warn patients about hyperglycaemia. Atazanavir, darunavir, fosamprenavir or tipranavir may be safer ➣ For signs and symptoms of hyperglycaemia, see Clinical Features of Some Adverse Drug Interactions, Hyperglycaemia
PROTEASE INHIBITORS NATEGLINIDE, PIOGLITAZONE, REPAGLINIDE
≠ levels of these antidiabetic drugs Inhibition of CYP2C9-and CYP3A4mediated metabolism of nateglinide and CYP3A4-mediated metabolism of pioglitazone and repaglinide
Monitor blood sugar closely
PROTEASE INHIBITORS SULPHONYLUREAS ≠ effect of tolbutamide with ritonavir
Ritonavir is a potent inhibitor of CYP2C9, which metabolizes many sulphonylureas
PROTEASE INHIBITORS ANTIDIARRHOEAL DRUGS – LOPERAMIDE
≠ risk of adverse effects when loperamide is co-ingested with ritonavir
Ritonavir inhibits P-gp and CYP3A4
Monitor for clinical effect, and consider ↓ dose if necessary. Stop if there are signs of abdominal distension in HIV patients as toxic megacolon has been reported
PROTEASE INHIBITORS ANTIEMETICS – APREPITANT
≠ adverse effects of aprepitant with nelfinavir and ritonavir (with or without lopinavir)
Inhibition of CYP3A4-mediated metabolism of aprepitant
Use with caution; clinical significance unclear; monitor closely
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Mechanism Precautions
carbamazepine with protease inhibitors
Inhibition of CYP3A4-mediated metabolism of carbamazepine
Use with caution. Monitor carbamazepine levels and side-effects when initiating or changing treatment
PROTEASE INHIBITORS PHENYTOIN Possibly ↓ efficacy of phenytoin, with a risk of fits when it is co-administered with indinavir, nelfinavir or ritonavir (with or without lopinavir)
Uncertain; ↓ plasma levels of phenytoin
Use with caution. Monitor phenytoin levels weekly. Adjust doses at 7-10day intervals. Maximum suggested dose adjustment each time is 25 mg
PROTEASE INHIBITORS ANTIFUNGALS – AZOLES
PROTEASE INHIBITORS ITRACONAZOLE, KETOCONAZOLE
Possibly ≠ levels of ketoconazole by amprenavir, indinavir and ritonavir (with or without lopinavir). Conversely, indinavir, ritonavir and saquinavir levels are ≠ 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
PROTEASE INHIBITORS VORICONAZOLE ↓ 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 once a day) unless benefits outweigh risks
PROTEASE INHIBITORS ANTIHISTAMINES – ASTEMIZOLE, CHLORPHENAMINE, TERFENADINE
Possibly ≠ adverse effects with amprenavir, atazanavir, indinavir, ritonavir (with or without lopinavir), saquinavir and tipranavir
Inhibition of CYP3A4-mediated metabolism of astemizole; the risk is greatest in patients who are slow CYP2D6 metabolizers because chlorphenamine and terfenadine are also metabolized by this route
Avoid co-administration
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DRUGS TO TREAT INFECTIONS ANTIVIRALS – ANTIRETROVIRALS Protease inhibitors
Uncertain Avoid co-administration
PROTEASE INHIBITORS VASODILATOR ANTIHYPERTENSIVES
≠ adverse effects of bosentan by ritonavir
Inhibition of CYP3A4-mediated metabolism of bosentan
Co-administration not recommended
PROTEASE INHIBITORS ANTIMALARIALS – ARTEMETHER WITH LUMEFANTRINE
≠ artemether levels Uncertain; possibly inhibited metabolism
Avoid co-administration
PROTEASE INHIBITORS ANTIMIGRAINE DRUGS
PROTEASE INHIBITORS ERGOT ALKALOIDS ≠ ergotamine/methysergide levels, with risk of toxicity
↓ CYP3A4-mediated metabolism of ergot derivatives
Avoid co-administration
PROTEASE INHIBITORS 5-HT1 AGONISTS – ALMOTRIPTAN, ELETRIPTAN
Possibly ≠ adverse effects when almotriptan or eletriptan is co-administered with indinavir, ritonavir (with or without lopinavir) or nelfinavir
Inhibition of CYP3A4-and possibly CYP2D6-mediated metabolism of eletriptan and CYP3A4-mediated metabolism of almotriptan
Avoid co-administration
PROTEASE INHIBITORS ANTIMUSCARINICS
PROTEASE INHIBITORS SOLIFENACIN ≠ adverse effects with nelfinavir and ritonavir (with or without lopinavir)
Inhibition of CYP3A4-mediated metabolism of solifenacin
Limit maximum dose of solifenacin to 5 mg daily
PROTEASE INHIBITORS TOLTERODINE Possibly ≠ adverse effects, including arrythmias with protease inhibitors
Inhibition of CYP2D6-and CYP3A4-mediated metabolism of tolterodine
Avoid co-administration
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Mechanism Precautions
HALOPERIDOL, CLOZAPINE, PIMOZIDE, RISPERIDONE, SERTINDOLE, THIORIDAZINE
≠ Inhibition of CYP3A4-and/or CYP2D6-mediated metabolism
Avoid co-administration of clozapine with ritonavir, and pimozide or sertindole with protease inhibitors. Use other antipsychotics with caution; ↓ dose may be required. With risperidone, watch closely for extrapyramidal side-effects and neuroepileptic malignant syndrome
PROTEASE INHIBITORS OLANZAPINE Possibly ↓ efficacy of olanzapine when co-ingested with ritonavir (with or without lopinavir)
Possibly ≠ metabolism via CYP1A2 and glucuronyl transferases
Monitor clinical response; ≠ dose as necessary
PROTEASE INHIBITORS
PROTEASE INHIBITORS ANTIVIRALS – FOSCARNET SODIUM
↓ renal function when co-administered with ritonavir or saquinavir
Uncertain; possibly ↓ renal excretion of foscarnet
Monitor renal function closely
PROTEASE INHIBITORS NNRTIs
AMPRENAVIR EFAVIRENZ Possible ↓ efficacy of amprenavir Uncertain; ↓ bioavailability of amprenavir
Consider ≠ dose of amprenavir to 1200 mg three times a day, or combine amprenavir 600 mg twice a day with ritonavir 100 mg twice a day
AMPRENAVIR NEVIRAPINE Efficacy of amprenavir predicted to be ↓
Uncertain; ↓ bioavailability of amprenavir
Monitor viral load
ATAZANAVIR EFAVIRENZ ↓ efficacy of efavirenz ≠ CYP3A4-mediated metabolism of efavirenz
Recommended dose of atazanavir is 400 mg when given with efavirenz 600 mg. Optimal suggested treatment is this combination plus ritonavir 100 mg daily
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DRUGS TO TREAT INFECTIONS ANTIVIRALS – ANTIRETROVIRALS Protease inhibitors
Atazanavir is a substrate and inhibitor of CYP3A4
Avoid concomitant use
≠ CYP3A4-mediated metabolism of indinavir
Monitor viral load; consider ≠ dose of indinavir to 1000 mg 8-hourly
LOPINAVIR AND RITONAVIR
NNRTIs Possible ↓ efficacy of lopinavir/ritonavir
Uncertain; ↓ bioavailability Consider ≠ lopinavir/ritonavir dose (by 33% with efavirenz and to 53 mg/133 mg twice daily, and monitor drug concentrations, with nevirapine). Monitor viral load closely as this ≠ dose may be insufficient. Monitor LFTs closely
NELFINAVIR EFAVIRENZ Possible ≠ efficacy of nelfinavir, with theoretical risk of adverse effects
Small ≠ bioavailability of nelfinavir No dose adjustment necessary
NELFINAVIR NEVIRAPINE Possible ↓ efficacy of nelfinavir Uncertain Dose adjustment probably not required, although one study suggests ≠ dose may be needed
RITONAVIR EFAVIRENZ ≠ efficacy and ≠ adverse effects of ritonavir, e.g. dizziness, nausea, paraesthesia, liver dysfunction
≠ bioavailability of ritonavir; competition for metabolism via CYP3A4
Combination is not well tolerated. Monitor closely, including LFTs. Lowdose ritonavir has not been studied
SAQUINAVIR EFAVIRENZ Possible ↓ efficacy of saquinavir, with risk of treatment failure
≠ CYP3A4-mediated metabolism of saquinavir
Combination is not recommended if saquinavir is the sole protease inhibitor; always use saquinavir in combination with another agent, e.g. ritonavir, when co-administering with efavirenz
SAQUINAVIR NEVIRAPINE Possible ↓ efficacy; risk of treatment failure of saquinavir
≠ CYP3A4-mediated metabolism of saquinavir
Clinical significance unclear. Different formulations of saquinavir may have different magnitudes of interaction
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Mechanism Precautions
atazanavir and indinavir
Absorption of these protease inhibitors may be affected by the buffered didanosine formulation, which ≠ gastric pH
Separate doses by at least 1 hour. Alternatively, consider using the enteric-coated formulation of didanosine
ATAZANAVIR TENOFOVIR ↓ efficacy of atazanavir Uncertain; ↓ plasma levels of atazanavir
Use with caution and consider using in combination with ritonavir
LOPINAVIR RITONAVIR ZIDOVUDINE ↓ efficacy of zidovudine ↓ plasma levels by ≠ glucuronidation
Avoid co-administration
NELFINAVIR STAVUDINE Possibly ≠ adverse effects Uncertain Warn patients that diarrhoea may occur
TIPRANAVIR RITONAVIR
ABACAVIR Possible ↓ efficacy; risk of treatment failure of abacavir
↓ plasma concentrations Not recommended unless there are no other available nucleoside reverse transcriptase inhibitors
TIPRANAVIR RITONAVIR
DIDANOSINE (ENTERICCOATED)
Possible ↓ efficacy of didanosine ↓ absorption Separate doses by at least 2 hours
TIPRANAVIR RITONAVIR
ZIDOVUDINE Possible ↓ efficacy; risk of treatment failure of zidovudine
↓ plasma concentrations Not recommended unless there are no other available nucleoside reverse transcriptase inhibitors
AMPRENAVIR RITONAVIR ≠ efficacy and ≠ adverse effects of both, e.g. ≠ triglycerides and creatine phosphokinase
Complex alterations in bioavailability. Ritonavir is a more potent CYP3A4 inhibitor than amprenavir, also inhibiting CYP2D6 and inducing CYP3A4, CYP1A2 and CYP2C9
Monitor closely. ↓ dose of both if used together; amprenavir 600 mg ritonavir 100 mg twice a day is suggested
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DRUGS TO TREAT INFECTIONS ANTIVIRALS – ANTIRETROVIRALS Protease inhibitors
≠
≠ bioavailability. Inhibition of metabolism via CYP3A4 by atazanavir; inhibition of UDGPT by indinavir
Avoid co-administration
ATAZANAVIR SAQUINAVIR ≠ efficacy and ≠ adverse effects of saquinavir
Inhibition of CYP3A4-mediated metabolism of saquinavir
Monitor more closely
INDINAVIR NELFINAVIR Possibly ≠ efficacy and ≠ adverse effects of both
Inhibition of CYP3A4-mediated metabolism
Uncertain if interaction is clinically significant; however, monitor more closely for adverse effects
INDINAVIR RITONAVIR ≠ efficacy and ≠ adverse effects of indinavir. Risk of nephrolithiasis if the dose of indinavir exceeds 800 mg twice a day
Inhibition of CYP3A4-mediated metabolism of indinavir
Dose of indinavir can be ↓ from 800 mg three times a day to 600 mg twice daily. Adequate hydration and monitoring are essential. Adults must drink at least 1500 mL/24 hours
INDINAVIR SAQUINAVIR Possibly ≠ efficacy and ≠ adverse effects of both
Inhibition of CYP3A4-mediated metabolism
Safety of combination not established. The formulation may affect the interaction. Monitor closely
NELFINAVIR RITONAVIR AND LOPINAVIR
Possibly ↓ efficacy of lopinavir and ritonavir, and ≠ efficacy of nelfinavir
↓ bioavailability of lopinavir and ritonavir, but ≠ minimum plasma levels of nelfinavir and its active metabolites
Monitor closely. May need to ≠ doses of lopinavir and ritonavir
NELFINAVIR RITONAVIR ≠ efficacy and ≠ adverse effects of nelfinavir; unclear effects on ritonavir
Involves CYP450 inhibition and induction. ≠ concentration of nelfinavir and its active metabolite M8
Monitor closely if combination used
NELFINAVIR SAQUINAVIR (SOFT GEL) Possibly ≠ efficacy and ≠ adverse effects, e.g. diarrhoea
Additive toxicity; ≠ bioavailability. Inhibition of metabolism via CYP3A4
Warn patients of ≠ side-effects
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Mechanism Precautions
Inhibition of CYP3A4-mediated
metabolism Dose of saquinavir can be ↓ from 1.2 g three times a day to 800 mg twice daily
SAQUINAVIR RITONAVIR ≠ efficacy and ≠ adverse effects of saquinavir; no clinically significant interaction for ritonavir
Large ≠ bioavailability of saquinavir via inhibition of CYP3A4 in gut wall and liver
Adjust dose and monitor closely. Saquinavir 1000 mg with ritonavir 100 mg twice a day is approximately equivalent to saquinavir 1200 mg three times a day on its own
TIPRANAVIR RITONAVIR
AMPRENAVIR RITONAVIR
Possibly ↓ efficacy Significant ↓ bioavailability Avoid co-administration
TIPRANAVIR RITONAVIR
ATAZANAVIR Possibly ↓ efficacy of atazanavir and ≠ toxicity of tipranavir ritonavir
Significant ↓ bioavailability Avoid co-administration
TIPRANAVIR RITONAVIR
LOPINAVIR RITONAVIR Possibly ↓ efficacy Significant ↓ bioavailability Avoid co-administration
TIPRANAVIR RITONAVIR
SAQUINAVIR RITONAVIR Possibly ↓ efficacy Significant ↓ bioavailability Avoid co-administration
PROTEASE INHIBITORS ANXIOLYTICS AND HYPNOTICS – BZDs, BUSPIRONE
≠ adverse effects, e.g. prolonged sedation
Inhibition of CYP3A4-mediated metabolism of BZDs and buspirone
Watch closely for ≠ sedation; ↓ dose of sedative as necessary. Some recommend considering substituting long-acting for shorter-acting BZDs with less active metabolites (e.g. lorazepam for diazepam)
RITONAVIR, TIPRANAVIR BETA-BLOCKERS ≠ adverse effects of carvedilol, metoprolol, propanolol and timolol
Inhibition of CYP2D6-mediated metabolism of these beta-blockers
Use an alternative beta-blocker if possible; if not, monitor closely. Avoid co-administration of metoprolol with ritonavir tipranavir
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DRUGS TO TREAT INFECTIONS ANTIVIRALS – ANTIRETROVIRALS Protease inhibitors
Inhibition of metabolism via CYP3A4 but mainly metabolized via CYP1A2, which is not inhibited
Not thought to be clinically significant; however, monitor levels more closely in unstable patients
RITONAVIR ( LOPINAVIR)
THEOPHYLLINE ↓ efficacy ≠ metabolism via induction of CYP1A2 also altered metabolism via CYP3A4
Monitor clinical response. Measure levels weekly after starting; ≠ doses may be required
PROTEASE INHIBITORS CALCIUM CHANNEL BLOCKERS
Plasma concentrations of calcium channel blockers are ≠ by protease inhibitors
Protease inhibitors inhibit CYP3A4-mediated metabolism of calcium channel blockers
Monitor PR, BP and ECG closely; ↓ dose of calcium channel blocker if necessary (e.g. manufacturers of diltiazem suggest starting at 50% of the standard dose and titrating to effect)
RITONAVIR (WITH OR WITHOUT LOPINAVIR)
CARDIAC GLYCOSIDES – DIGOXIN
Plasma digoxin concentrations may be ≠ by ritonavir
Uncertain; probably due to inhibition of P-gp-mediated renal excretion of digoxin and ≠ intestinal absorption
Monitor digoxin levels; watch for digoxin toxicity
INDINAVIR, NELFINAVIR, RITONAVIR, SAQUINAVIR
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
PROTEASE INHIBITORS DIURETICS – POTASSIUMSPARING
Possibly ≠ adverse effects of eplerenone with nelfinavir, ritonavir (with or without lopinavir) and saquinavir
Inhibition of CYP3A4-mediated metabolism of eplerenone
Avoid concomitant use
PROTEASE INHIBITORS DRUG DEPENDENCE THERAPIES
PROTEASE INHIBITORS BUPROPION ≠ adverse effects of bupropion with nelfinavir and ritonavir (with or without lopinavir)
Possibly inhibition of CYP2B6mediated metabolism of bupropion
Avoid co-administration
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Mechanism Precautions
Ritonavir and lopinavir/ritonavir oral solutions contain 43% alcohol
Warn patients. Consider using capsule preparation as an alternative
PROTEASE INHIBITORS DUTASTERIDE Possibly ≠ adverse effects of dutasteride with indinavir or ritonavir (with or without lopinavir)
Inhibition of CYP3A4-mediated metabolism of dutasteride
Monitor closely; ↓ dosing frequency if side-effects occur
SAQUINAVIR (INVIRASE HARD CAPSULES)
GRAPEFRUIT JUICE Possibly ≠ efficacy Possibly ≠ bioavailability; ↓ presystemic metabolism. Constituents of grapefruit irreversibly inhibit intestinal cytochrome CYP3A4. Transport via P-gp and MRP-2 efflux pumps is also inhibited
No dose adjustment is advised. Oral bioavailability is very low and is enhanced beneficially with grapefruit juice or grapefruit. Soft gel capsules have greater bioavailability so may interact to a lesser degree
AMPRENAVIR, ATAZANAVIR
H2 RECEPTOR BLOCKERS – CIMETIDINE
↓ efficacy of amprenavir; possible ≠ levels of cimetidine
↓ absorption of amprenavir and atazanavir. Uncertain mechanism of action on cimetidine
Amprenavir: separate doses by at least 1 hour. Take atazanavir at least 2 hours before or 10 hours after the H2 blocker. In both cases, monitor viral load closely
PROTEASE INHIBITORS IVABRADINE ≠ levels with nelfinavir and ritonavir Uncertain Avoid co-administration PROTEASE INHIBITORS LIPID-LOWERING DRUGS – STATINS
PROTEASE INHIBITORS ATORVASTATIN ≠ efficacy and ≠ risk of adverse effects of atorvastatin
Inhibition of CYP3A4-mediated metabolism of atorvastatin
Use with caution. Monitor for atorvastatin toxicity, and monitor CK. Inform patients and ↓ dose if necessary or start with 10 mg once daily. Use the lowest dose possible to attain the target low-density lipoprotein ↓. Alternatives are pravastatin and fluvastatin
D R
U G
STO TR
EA TIN
FEC TIO
N S
A N
TIV IR
A LS-A
N TIR
ETR O
V IR
A LS627
DRUGS TO TREAT INFECTIONS ANTIVIRALS – ANTIRETROVIRALS Protease inhibitors
Inhibition of CYP3A4-mediated metabolism of these statins
Avoid co-administration
nelfinavir and ritonavir
Induction of metabolism of oestrogens
Advise patients to use additional contraception for the period of intake and for 1 month after stopping co-administration with nelfinavir and ritonavir. Barrier methods are necessary to prevent transmission of infection from patients with HIV
PROTEASE INHIBITORS PERIPHERAL VASODILATORS
Amprenavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir ≠ cilostazol levels
These protease inhibitors inhibit CYP3A4-mediated metabolism of cilostazol
Avoid co-administration
PROTEASE INHIBITORS PHOSPHODIESTERASE TYPE 5 INHIBITORS – SILDENAFIL, TADALAFIL, VARDENAFIL
≠ sildenafil, tadalafil and vardenafil levels
Inhibition of CYP3A4-and possibly CYP2C9-mediated metabolism of sildenafil
Use with caution; monitor BP closely. UK manufacturers recommend avoiding co-administration of vardenafil with protease inhibitors in patients 75 years. US manufacturers recommend using with caution, starting with a daily dose of 2.5 mg
PROTEASE INHIBITORS PROGESTOGENS – NORETHISTERONE
≠ adverse effects with amprenavir and atazanavir. Possibly ↓ efficacy and risk of contraceptive failure with nelfinavir and ritonavir (with or without lopinavir)
Uncertain Advise patients to use additional contraception for the period of intake and for 1 month after stopping coadministration with these drugs. Barrier methods are necessary to prevent transmission of infection from patients with HIV. Watch for early features of toxicity of amprenavir and atazanavir, and adjust the dose accordingly
