chapter
Antivirals – antiretrovirals
Pages 32

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