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Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children

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Table 5. Significant Drug Interactions for Drugs Used to Treat or Prevent Opportunistic Infections

(Last updated:11/6/2013; last reviewed:11/6/2013)

There is the potential for significant drug interactions and overlapping toxicities in patients receiving medications for treatment or prevention of opportunistic infections (OIs). These patients often are receiving other medications, including antiretrovirals that interfere with metabolism or elimination of OI medications. In particular, protease inhibitors and non-nucleoside reverse transcriptase inhibitors affect the CYP450 or other transporter systems and may be associated with clinically significant drug interactions. The integrase inhibitor raltegravir is metabolized by UGT1A1 and may be a suitable option when trying to minimize interactions with other drug classes. 

Table 5 provides clinicians with information regarding known or suspected drug interactions between drugs commonly used for treatment or prevention of HIV-associated OIs and treatment of HIV infection. Drug interaction information is generally obtained from studies involving healthy adult volunteers. Some pharmacokinetic (PK) data are available from studies involving HIV-infected adults, whereas data in children are extremely limited. New information continues to become available and it is important to carefully review a patient’s current medications, including prescription and over-the-counter medications. It is difficult to predict the interaction potential when three or more drugs with similar metabolic pathways are co-administered and there is substantial inter-patient variability in the magnitude of these interactions. When possible, alternative agents with less drug interaction potential or use of therapeutic drug monitoring should be considered. 

Table 5 contains only a partial listing of drug interactions for drugs used to treat or prevent OIs. The links below are excellent resources for investigating the potential for drug interactions. These tools include more comprehensive information and provide up-to-date information as new PK data become available. 

http://www.hiv-druginteractions.org/
http://tdm.pharm.buffalo.edu/home/di_search/
http://www.aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/32/drug-interactions/
http://www.drugs.com/drug_interactions.html
http://hivinsite.ucsf.edu/InSite?page=ar-00-02
http://www.nynjaetc.org/clinical_support.html 
http://www.clinicaloptions.com/inPractice.aspx
http://epocrates.com

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Table 5: Significant Drug Interactions for Drugs Used to Treat or Prevent Opportunistic Infections
Drug Name Overlapping Toxicities Recommendation
* The drug interactions included in this table were selected on the basis of their potential clinical significance and are not inclusive of all potential drug interactions (see drug label and the drug interaction websites listed for complete information on drug interactions).
Acyclovir
(Zovirax)
Overlapping Toxicities:
  • Nephrotoxic drugs
Monitor for toxicities of these drugs.
Increased Concentrations (Both Drugs) and Overlapping Toxicities:
  • Antivirals: valacyclovir, valganciclovir, ganciclovir, cidofovir
  • ARVs: tenofovir
Monitor for toxicities of these drugs.
Albendazole
Increases Albendazole Concentrations:
  • Anthelmintic drugs: praziquantel
Caution advised.
Amikacin
Overlapping Toxicities:
  • Anti-tuberculosis drugs (injectable): streptomycin, kanamycin
  • Nephrotoxic or ototoxic drugs
  • Antimycobacterial drugs: capreomycin
  • Antivirals: cidofovir
Caution advised. Avoid combination of amikacin and cidofovir.
Amphotericin B 
Amphotericin B Lipid Complex 
(Abelcet)

Amphotericin B Liposome
(Ambisome)
Overlapping Toxicities:
  • Bone marrow suppressant drugs: corticosteroids
  • Nephrotoxic drugs
  • Neuromuscular blocking drugs
Caution advised.
Atovaquone
Decreases Atovaquone Concentrations:
  • Antimycobacterial drugs: rifampin, rifabutin
  • ARVs: lopinavir/ritonavir, atazanavir/ritonavir
  • Antibiotics: doxycycline
Co-administration of atovaquone and rifampin should be avoided.
Azithromycin
Overlapping Toxicities:
  • Artemether/lumefantrine, chloroquine, quinine
Caution advised. Increased risk of QT prolongation.
Boceprevir
Please see Adult OI guidelines for information about drug interactions, including warnings about interactions between boceprevir and HIV protease inhibitors.
Capreomycin
Overlapping Toxicities:
  • Nephrotoxic or ototoxic drugs
  • Neuromuscular blocking drugs
  • Antibacterial drugs: aminoglycosides (parenteral)
Caution advised.
Caspofungin
Decreases Caspofungin Concentrations:
  • Anticonvulsant drugs: phenytoin
  • Antimycobacterial drugs: rifampin
  • ARV drugs: efavirenz, nevirapine
Increase in dose of caspofungin is recommended when co-administered with CYP450 inducers.
Cidofovir
Overlapping Toxicities:
  • Antibacterial drugs: aminoglycosides
  • Antiviral drugs: foscarnet
  • Nephrotoxic drugs
Monitor for toxicities of these drugs.
Ciprofloxacin
Decreases Ciprofloxacin Absorption:
  • ARV drugs: didanosine
  • Minerals: ferrous sulfate, zinc
  • Gastrointestinal drugs: antacids, sucralfate, magnesium-containing laxatives
Give oral ciprofloxacin 2 hours before or 6 hours after drugs that may interfere with absorption.
Overlapping Toxicities
  • Artemether/lumefantrine, clarithromycin, quinine
Caution advised.
Clarithromycin
Increases Clarithromycin Concentrations:
  • ARV drugs: atazanavir/ritonavir, lopinavir/ritonavir
  • Antifungals: itraconazole (itraconazole concentrations also increased)
Caution advised. Concern for QTc prolongation.
Decrease clarithromycin dose or consider switching to azithromycin,
which has less potential for drug interactions.
Increases Concentration of Other Medications:
  • ARV drugs: etravirine
Consider alternative agent.
Decreases Clarithromycin Concentrations:
  • ARV drugs: efavirenz, etravirine, nevirapine
  • Antimycobacterial drugs: rifampin, rifabutin (rifabutin concentrations also increased)
Consider switching to azithromycin, which has less potential for drug interaction.

For concomitant use of rifabutin and clarithromycin, consider decreasing dose of rifabutin or switching to azithromycin.
Clindamycin
Decreases Clindamycin Antibacterial Efficacy:
  • Antibacterial drugs: chloramphenicol, erythromycins
Avoid concomitant use.
Cycloserine
Overlapping Toxicities:
  • Antimycobacterial drugs: ethionamide, isoniazid
Caution advised.
Dapsone Decreases Dapsone Concentrations:
  • Antimycobacterial drugs: rifampin 
Co-administration should be avoided if possible. Consider alternatives for dapsone or use rifabutin.
Decreases Dapsone Absorption:
  • ARV drugs: didanosine suspension
  • Gastrointestinal drugs: antacids
For co-administration with antacids or didanosine suspension, give dapsone 1 hour before or 4 hours after the other medication.
Overlapping Toxicities:
  • Bone marrow suppressant drugs or drugs associated with hemolysis
Caution advised.
Doxycycline
Decreases Doxycycline Concentrations:
  • Anticonvulsant drugs: phenytoin, carbamazepine
  • Antimycobacterial drugs: rifampin
Potential for decreased doxycycline efficacy. Monitor for therapeutic failure.
Erythromycin
Increases Concentrations of Erythromycin and Co-Administered Medication:
  • Antifungals: itraconazole
Monitor for toxicities of both drugs, potential for QT prolongation.
Ethambutol
Overlapping Toxicities:
  • Neurotoxic drugs
Caution advised.
Ethionamide
Potential for Increased Toxicity Due to Overlapping Toxicity:
  • Neurotoxic drugs
  • Antimycobacterial drugs: cycloserine, isoniazid
Caution advised.
Fluconazole
Decreases Fluconazole Levels:
  • Anticonvulsant drugs: phenytoin
  • Antimycobacterial drugs: rifampin
  • ARV drugs: rilpivirine
Monitor for efficacy. May need to increase fluconazole dose.
Increases Concomitant Drug Concentrations:
  • ARV drugs: saquinavir, tipranavir, nevirapine, and etravirine 
May need to decrease dose of saquinavir. Avoid tipranivir with high doses of fluconazole (maximum fluconazole dose in adults: 200 mg). Caution advised with etravirine.
  • Antimycobacterial drugs: rifabutin
May need to decrease dose of rifabutin.
  • Statins: simvastatin, lovastatin, atorvastatin
Do not co-administer with simvastatin or lovastatin. Avoid use of atorvastatin if possible. Alternative statins such as fluvastatin, rosuvastatin, pravastatin are preferred or discontinue statin during antifungal therapy.
Flucytosine
Increases Flucytosine Concentrations:
  • Nephrotoxic drugs
Caution advised.
Foscarnet
Overlapping Toxicities:
  • Antiviral drugs: cidofovir
  • Anti-pneumocystis drugs: pentamidine
  • Nephrotoxic drugs
Monitor for toxicities of these drugs.
Ganciclovir
Increases Ganciclovir Concentrations :
  • ARV drugs: tenofovir (concentrations also increased)
Monitor for toxicities of these drugs.
Increases Concomitant Drug Concentrations:
  • ARV drugs: didanosine, tenofovir
Caution advised.
Overlapping Toxicities:
  • Antibacterial drugs: imipenem-cilastatin
  • ARV drugs: zidovudine
  • Bone marrow suppressant drugs
  • Nephrotoxic drugs
Caution advised. Increased risk of seizures with imipenem-cilastatin.
Interferon-Alfa
Overlapping Toxicities:
  • ARV drugs: zidovudine, lamivudine
  • Bone marrow suppressant drugs
Co-administration of zidovudine and lamivudine should be avoided if possible. Caution advised with other bone marrow suppressant drugs.
Isoniazid
Decreases Isoniazid Concentrations:
  • Corticosteroids: glucocorticoids (e.g., prednisolone)
Use with caution.
Decreases Isoniazid Absorption:
  • Gastrointestinal drugs: antacids
Caution advised.
Increases Concomitant Drug Concentrations:
  • Diazepam
Caution advised.
Decreases Concomitant Drug Concentrations:
  • Antifungal drugs: ketoconazole, itraconazole
Co-administration should be avoided, if possible.
Overlapping Toxicities:
  • Antimycobacterial drugs: rifampin, cycloserine, ethionamide
  • Hepatotoxic drugs
  • Neurotoxic drugs
Caution advised.
Itraconazole
Increases Itraconazole Concentration:
  • Antibacterial: clarithromycin, erythromycin, ciprofloxacin
  • ARVs: protease inhibitors
Monitor for toxicities. Monitor itraconazole concentration. Consider azithromycin instead of other macrolides. High doses of itraconazole are not recommended with PIs.
Increases Concomitant Drug Concentrations:
  • ARV drugs: etravirine, maraviroc, protease inhibitors
Caution advised. Monitor for toxicities. Decrease adult maraviroc dose to 150 mg twice daily.
  • Statins: lovastatin, simvastatin, atorvastatin
Do not co-administer with simvastatin or lovastatin. Avoid use of atorvastatin if possible. Alternative statins such as fluvastatin, rosuvastatin, pravastatin are preferred or discontinue statin during antifungal therapy.
  • Antibacterial: clarithromycin, erythromycin
Consider switching to azithromycin, which has less potential for drug interaction.
  • Sedatives/hypnotics: midazolam, alprazolam, diazepam
Co-administration of midazolam and alprazolam should be avoided. Co-administration of diazepam should be avoided, if possible.
  • Cardiac: quinidine
Co-administration of quinidine should be avoided. QT prolongation.
Decreases Itraconazole Concentrations:
  • ARV drugs: efavirenz, etravirine, nevirapine, rilpivirine
Monitor itraconazole concentration. Co-administration of efavirenz should be avoided if possible.
  • Anticonvulsant drugs: carbamazepine, (fos)phenytoin
Monitor itraconazole concentration.
  • Antimycobacterial drugs: rifampin, rifabutin, rifapentine, isoniazid
Co-administration with rifampin should be avoided. Co-administration with rifabutin should be avoided, if possible. Monitor for toxicities. Monitor itraconazole concentration.
Decreases Itraconazole Absorption:
  • ARV drugs: didanosine
  • Gastrointestinal drugs: antacids, anticholinergics/antispasmodics, histamine H2-receptor antagonists, omeprazole, sucralfate
Monitor itraconazole concentration.
Lumefantrine
Increases Concomitant Drug Levels:
  • ARV drugs: nevirapine
Monitor for nevirapine toxicity.
Overlapping Toxicities:
  • ARV drugs: protease inhibitors
  • Antibacterial drugs: macrolides, fluoroquinolones
  • Antifungal drugs: fluconazole, voriconazole
  • Antimalarial drugs: quinine, quinidine
  • Psychotropic drugs: quetiapine, tricyclic antidepressants
Co-administration with fluconazole or voriconazole should be avoided. For all other drugs, co-administration should be avoided, if possible; monitor for toxicities (QT prolongation). 
Mefloquine
Decreases Mefloquine Concentrations:
  • Antimalarial drugs: quinine
  • Antimycobacterial: rifampin
Monitor for decreased mefloquine efficacy.
Co-administration of rifampin should be avoided, if possible; use rifabutin instead.
Decreases Concomitant Drug Concentrations:
  • ARV drugs: ritonavir, possibly other protease inhibitors
Monitor for virologic failure of protease inhibitor-containing ART regimen.
Overlapping Toxicities:
  • Anti-malarial drugs: quinine
  • Other drugs that can cause prolonged QT
Avoid co-administration, if possible. Monitor for toxicities (EKG changes, cardiac arrest; also seizures with quinine). If co-administered with quinine, give mefloquine at least 12 hours after last dose of quinine.
Nitazoxanide
Increases Concomitant Drug Concentrations:
  • Phenytoin 
Potential for interaction with other medications that are highly protein bound. Use with caution as interaction will increase concentrations of concomitant medication.
Paromomycin
Overlapping Toxicities:
  • Neuromuscular blocking drugs
Use with caution.
Pentamidine
Overlapping Toxicities:
  • Antiviral drugs: foscarnet
Co-administration should be avoided, if possible. Monitor for toxicities (hypocalcaemia, QT prolongation).
  • ARV drugs: protease inhibitors, didanosine
Co-administration should be avoided, if possible. Monitor for toxicities (QT prolongation with protease inhibitors; pancreatitis for didanosine).
  • Bone marrow suppressant drugs
Monitor for toxicities.
  • Nephrotoxic drugs
Monitor for toxicities.
  • Other drugs that can cause prolonged QT
Monitor for toxicities. Avoid co-administration, if possible.
Posaconazole
Decreases Posaconazole Drug Concentrations:
  • ARV drugs: efavirenz, fosamprenavir, rilpivirine
Co-administration of fosamprenavir should be avoided. Co-administration of efavirenz should be avoided, if possible. If co-administered, monitor posaconazole concentrations and adjust dose accordingly.
  • Anticonvulsant drugs: phenytoin
Co-administration should be avoided, if possible. If co-administered, monitor posaconazole concentrations and adjust dose accordingly.
  • Antimycobacterial drugs: rifabutin, rifampin
Co-administration should be avoided, if possible. If co-administered, monitor posaconazole concentrations and adjust dose accordingly.
Increases Concomitant Drug Concentrations:
  • ARV drugs: atazanavir, saquinavir, lopinavir, etravirine, and ritonavir
Co-administration should be avoided, if possible. Monitor for toxicities. Consider monitoring concentrations and adjust dose as necessary.
  • Antibacterial drugs: erythromycin, clarithromycin
Co-administration should be avoided.
  • Anticonvulsant drugs: phenytoin
Co-administration should be avoided.
  • Sedatives/hypnotics: midazolam, alprazolam, diazepam
Co-administration should be avoided, if possible. Monitor for toxicities.
  • Antimycobacterial drugs: rifabutin
Co-administration should be avoided.
  • Statins: simvastatin, lovastatin, atorvastatin
Do not co-administer with simvastatin or lovastatin. Avoid use of atorvastatin if possible. Alternative statins such as fluvastatin, rosuvastatin, pravastatin are preferred or discontinue statin during antifungal therapy.
  • Antimalarials: Quinidine, quinine, mefloquine, lumefantrine, halofantrine
Co-administration should be avoided.
Decreases Concomitant Drug Concentrations:
  • ARV drugs: fosamprenavir
Co-administration should be avoided.
  • Other drugs that can cause prolonged QT
Use with caution. Monitor for toxicities.
Proguanil
Decreases Proguanil Concentrations:
  • Atazanavir/ritonavir, lopinavir/ritonavir, efavirenz
Use with caution.
Pyrazinamide
Overlapping Toxicities:
  • Antimycobacterial drugs: rifampin, ethionamide
  • Hepatotoxic drugs
Use with caution. Monitor for hepatotoxicity.
Quinidine
Increases Quinidine Concentrations:
  • Protease inhibitors
Co-administration of PIs should be avoided. Increased risk of arrhythmia. Co-administration may be necessary in presence of life-threatening, severe malaria and in the absence of other therapy, while artesunate is obtained from the CDC.
  • Itraconazole, posaconazole, voriconazole
Co-administration should be avoided. Increased risk of arrhythmia.
Decreases Quinidine Concentrations:
  • Etravirine
Use with caution. Monitor quinidine levels.
Increases Concomitant Drug Concentrations:
  • Tricyclic antidepressants
Co-administration should be avoided, if possible. Monitor for toxicities.
Overlapping Toxicities:
  • Other drugs that can prolong QT interval
Co-administration should be avoided, if possible. Monitor for toxicities (QT prolongation).
Ribavirin
Increases Concentrations Of Concomitant Drug:
  • ARV drugs: didanosine
Co-administration should be avoided. Potential for increased risk of pancreatitis and mitochondrial toxicity.
Decreases Concentrations of Concomitant Drug:
  • Zidovudine, stavudine
Co-administration should be avoided, if possible.
Overlapping Toxicities:
  • Zidovudine, all NRTIs
Co-administration should be avoided, if possible. Monitor for toxicities (anemia for zidovudine; lactic acidosis for all NRTIs).
Rifabutin
Increases Rifabutin Concentrations:
  • HIV protease inhibitors 
Use with caution. Monitor for rifabutin toxicity. Reduce rifabutin dose if co-administered with PIs.
  • Fluconazole
Use with caution. Monitor for rifabutin toxicity. Consider rifabutin dose reduction.
  • Voriconazole, itraconazole, posaconazole
Co-administration should be avoided, if possible. If co-administered, consider TDM and monitor for rifabutin toxicities (and azole clinical efficacy).
  • Clarithromycin
Co-administration should be avoided, if possible. Monitor for rifabutin toxicity. Consider rifabutin dose reduction or using azithromycin instead.
Increases Concomitant Drug Concentrations:
  • Didanosine
Use with caution. Monitor for didanosine toxicity.
Decreases Rifabutin Concentrations:
  • Efavirenz, etravirine
Use with caution. Higher rifabutin dose required when efavirenz co-administered. Consider TDM.
Decreases Concomitant Drug Concentrations:
  • ARV drugs: rilpivirine
Co-administration should be avoided. 
  • ARV drugs: saquinavir, etravirine, maraviroc
Co-administration should be avoided, if possible.
  • Antibacterial drugs: dapsone, atovaquone
Use with caution. Monitor for dapsone treatment failure.
  • Antifungal drugs: azoles (except for fluconazole) 
Co-administration should be avoided, if possible. If co-administered, consider TDM and monitor for rifabutin toxicities (and azole clinical efficacy).
  • Contraceptives: oral
Oral contraceptives less effective. Additional non-hormonal contraceptive or alternative recommended.
Rifampin
Decreases Concomitant Drug Concentrations:
  • Contraceptives: oral
Oral contraceptives less effective. Additional non-hormonal contraceptive or alternative recommended.
  • ARV drugs: PIs ± ritonavir, nevirapine, raltegravir, rilpivirine
Significantly decreases PI exposure; co-administration should be avoided. Nevirapine: use only if other options not available and close virologic and immunologic monitoring can be done; consider efavirenz instead. Raltegravir dose increase may be required. Rilpivirine co-administration should be avoided.
  • Antimicrobial: atovaquone, dapsone, clarithromycin, doxycycline
Co-administration of atovaquone and rifampin should be avoided. Consider switching clarithromycin to azithromycin, which has less potential for drug interaction. Dapsone and Doxycycline efficacy may be reduced .
  • Antifungal drugs: azoles, caspofungin
Increase in dose of caspofungin is recommended when co-administered with CYP450 inducers. 

Azoles: Monitor for efficacy. May need to increase antifungal dose
  • Other: corticosteroids, methadone
Caution advised with corticosteroids (decreased efficacy). 

Methadone: Monitor for efficacy and/or opiate withdrawal symptoms with methadone.
Overlapping Toxicities:
  • Bone marrow suppressant drugs
  • Hepatotoxic drugs
Monitor for toxicities of these drugs.
Streptomycin
Potential for Increased Toxicity Due to Overlapping Toxicity:
  • Nephrotoxic drugs
  • Neuromuscular blocking drugs
Monitor for toxicities of these drugs.
Telaprevir
Please see Adult OI guidelines for information about drug interactions, including warnings about interactions between telaprevir and HIV protease inhibitors. Caution advised.
Trimethoprim-Sulfamethoxazole
Overlapping Toxicities:
  • Folate antagonists
  • Bone marrow suppressant drugs
Monitor for toxicities of these drugs.
Valacyclovir
Potential For Increased Concentrations (of Both Drugs) and Overlapping Toxicity:
  • Antivirals: acyclovir, valganciclovir, ganciclovir, cidofovir
  • ARVs: tenofovir
Monitor for toxicities of these drugs.
Valganciclovir
Potential for Increased Concentrations (of Both Drugs) and Overlapping Toxicity:
  • Antivirals: valacyclovir, acyclovir, ganciclovir, cidofovir
  • ARVs: tenofovir
Monitor for toxicities of these drugs.
Voriconazole
Decreases Voriconazole Concentrations:
  • Anticonvulsant drugs: carbamazepine, long-acting barbiturates
Caution advised.
  • Antimycobacterial drugs: rifabutin, rifampin
Rifabutin and Rifampin co-administration should be avoided.
  • ARV drugs: efavirenz, nevirapine, PIs boosted with ritonavir
Standard doses of efavirenz and voriconazole should not be used; voriconazole dose may need to be increased and efavirenz dose decreased, or use alternative antifungal agent. 

Potential for increased PI concentrations and decreased voriconazole concentrations; consider monitoring voriconazole concentrations and adjust dose accordingly; monitor for PI-associated toxicities or consider using an alternative antifungal agent.
Increases Voriconazole Concentrations:
  • ARV drugs: etravirine
Monitor voriconazole concentrations to reduce toxicity. 
Increases Concomitant Drug Concentrations:
  • Antimycobacterial drugs: rifabutin
Caution advised.
  • ARV drugs: protease inhibitors boosted with ritonavir, efavirenz, etravirine
Caution advised.
  • Statins: simvastatin, lovastatin, atorvastatin
Statins: Do not co-administer with simvastatin or lovastatin. Avoid use of atorvastatin if possible. Alternative statins such as fluvastatin, rosuvastatin, pravastatin are preferred or discontinue statin during antifungal therapy.
  • Sedatives/hypnotics: midazolam, alprazolam, triazolam
Co-administration should be avoided if possible. Monitor for toxicities.
Key to Acronyms: ART = antiretroviral therapy; ARV = antiretroviral; CDC = Centers for Disease Control and Prevention; EKG = electrocardiogram; NNRTI = non-nucleoside reverse transcriptase inhibitors; NRTI = nucleoside reverse transcriptase inhibitors; OI = opportunistic infection; PI = protease inhibitors; PK = pharmacokinetic; TDM = therapeutic drug monitoring

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