CHAPTER 7 – ANTIRETROVIRAL DRUG INTERACTIONS 69

CHAPTER 7 – ANTIRETROVIRAL DRUG

INTERACTIONS
Joanne J. Orrick, PharmD, BCPS
Clinical Specialist, Infectious Diseases Shands at the University of Florida, Gainesville and
Clinical Assistant Professor, University of Florida College of Pharmacy, Gainesville

The practitioner involved in the care of HIV-infected patients who are receiving highly active antiretroviral therapy will
frequently encounter problems related to the detection and management of drug interactions. The clinician should contact
multiple resources when determining the existence or possible clinical significance of a potential drug interaction. Whenever
possible in vivo data should be sought since drug interactions predicted in vitro do not always occur in vivo. If in vivo data is
not available, the clinician should predict the potential for a drug-drug interaction based on the route of elimination and
metabolism of each drug and the potential for each drug to inhibit or induce hepatic enzymes or interfere with renal
elimination. In addition, the clinical significance of the interaction and the availability of alternative treatment options should
also be evaluated (see Figure 1).

Figure 1 – Identifying/Managing Antiretroviral Drug Interactions

Identify Potential Drug Interaction
• Consult resources (i.e. textbooks, guidelines,
conference abstracts, manufacturer)
• Predict potential interactions (i.e. based on
metabolism pathways and enzyme
inhibiting/inducing properties

$
Verify Existence of Interaction
• Documentation of interactions in PK studies
• Time course of interaction (if interaction has
already occurred, effects can be evaluated)

$
Assess Clinical Significance of Interaction
• Potential toxicity
• Risk of therapeutic failure or resistance

$
Evaluate Alternatives
• Alter administration times (i.e. for interactions
involving absorption)
• Dose adjustment of antiretroviral or other
agent (if data available)
• Change to another agent less likely to interact
• Add agent to counteract interaction
• Take no action/monitor for adverse outcome
of interaction (if likelihood of interaction is
low and/or potential clinical impact
insignificant)
Adapted from Tseng AL and Foisy M. Management of drug interactions in
patient with HIV. Ann Pharmacother 1997; 31:1040-58.

HIV/AIDS PRIMARY CARE GUIDE, FLORIDA AIDS EDUCATION AND TRAINING CENTER, UNIVERSITY OF FLOIRDA, 2002
70 CHAPTER 7 – ANTIRETROVIRAL DRUG INTERACTIONS

There are various types of drug interactions that must be considered. Pharmacodynamic drug interactions involve drugs
with overlapping activities which can be use advantageously to achieve synergistic activity or overlapping toxicities which
can produce unwanted side-effects. Pharmacokinetic (PK) drug interactions involve the absorption, distribution,
metabolism, and elimination of the drugs. Food or antacids can affect the absorption of certain drugs including many of the
antiretrovirals. Interactions that affect absorption can cause subtherapeutic antiretroviral levels leading to therapeutic failure.
Distribution drug interactions, which include protein binding displacement interactions, are not usually of clinical
significance. Drug interactions that involve metabolism include interactions that involve inhibition or induction of
metabolism. These interactions can be beneficial when one agent is used to inhibit the metabolism of a second agent thereby
achieving therapeutic levels of the second agent. These interactions can also be detrimental leading to therapeutic failure if
induction of metabolism occurs or toxicity if inhibition of metabolism occurs.

As a class, the nucleoside reverse transcriptase inhibitors (NRTIs) have minimal drug interactions as compared to the
nonnucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). The NRTIs mainly undergo renal
elimination with the exception of zidovudine and abacavir. Zidovudine undergoes glucuronidation and abacavir is
metabolized by alcohol dehydrogenase. Drug interactions with this class of agents mainly include pharmacodynamic
interactions involving agents with overlapping toxicities. The NNRTIs, delavirdine, nevirapine, and efavirenz, have varying
effects on the metabolism of other drugs. Delavirdine is a potent cytochrome P450 enzyme inhibitor. Nevirapine is a
cytochrome P450 3A enzyme inducer as well as an inducer of glucuronyl transferase. Drug interactions involving efavirenz
can be complex since it has the potential to inhibitor or induce cytochrome P450 enzymes. All of the PIs inhibit the
cytochrome P450 enzyme system but do so to varying degrees. Ritonavir is the most potent cytochrome P450 enzyme
inhibitor in the class. See Table 1 for the enzymes by which the NNRTIs and PIs are metabolized and the enzymes induced or
inhibited by each agent. Tables 2, 3 and 4 below provide a comprehensive list of documented and potential drug interactions
with all of the currently approved antiretroviral agents. These tables provide the drug interaction, how to manage the
interaction (i.e. space the medication administration times, dosage adjustment, or alternative agent that may be safer to use),
as well as references.

NOTE: This list is not all-inclusive. The clinician should use sound clinical judgment
to predict drug interactions on the basis of the pharmacologic and kinetic
characteristics of each agent.

Table 1 – NNRTIs and PIs: Metabolism and Effects on Cytochrome P450 Enzymes
METABOLIZED BY ENZYMES INHIBITED ENZYMES INDUCED

NNRTIs
Rescriptor®
3A4 3A4 None
(Delavirdine, DLV)
Viramune® 3A4
3A4 None
(Nevirapine, NVP) glucuronyl transferase
Sustiva®
3A4 > 2B6 3A4, 2C9, 2C19 3A4
(Efavirenz, EFV)á
PIs
Agenerase® Unknown (May decrease
3A4 3A4
(Amprenavir, APV) levels of some OCs)
Crixivan®
3A4 3A4 None
(Indinavir, IDV)
Kaletra® 3A4 > 2D6 > 2C19 >> 2A6 > 3A, 1A2, 2C9, glucuronyl
3A4 > 2D6
(Lopinavir/ritonavir, KAL) 1A2 > 2E1 transferase
Viracept®
3A4 > > 2C19, 2D6, 2C9, 2E1 3A4 glucuronyl transferase
(Nelfinavir, NFV)
Norvir® 3A4 > 2D6 > 2C19 >> 2A6 > 3A, 1A2, 2C9, glucuronyl
3A4 > 2D6
(Ritonavir, RTV) 1A2 > 2E1 transferase
Fortovase®/Invirase®
3A4 3A4 None
(Saquinavir SGC/HGC, SQV)
áSustiva® can inhibit or induce the CYP 3A4 enzyme.

HIV/AIDS PRIMARY CARE GUIDE, FLORIDA AIDS EDUCATION AND TRAINING CENTER, UNIVERSITY OF FLOIRDA, 2002
 CHAPTER 7 – ANTIRETROVIRAL DRUG INTERACTIONS 71

Table 2 – Nucleoside/Nucleotide Reverse Transcriptase Inhibitor (NRTI) Drug Interactions

ZIAGEN® (ABACAVIR)
Inhibits: none
Induces: none
Metabolized by alcohol dehydrogenase
CONCOMITANT DRUG INTERACTION HOW TO MANAGE INTERACTION
Competition for metabolism via alcohol
Alcohol Inform patient to limit alcohol intake
dehydrogenase ↑ abacavir AUC by 41%

VIDEX®, VIDEX EC® (DIDANOSINE, DDI)

Inhibits: none
Induces: none
Undergoes mainly renal elimination
CONCOMITANT DRUG INTERACTION HOW TO MANAGE INTERACTION
Avoid ddI or monitor patients closely for the
Alcohol May ↑ risk of pancreatitis
development of pancreatitis
↑ ddI AUC 4-fold in 2 patients with renal failure; may
Allopurinol Monitor for ddI toxicity
increase risk of pancreatitis
Tablet formulation contains aluminum/magnesium
Antacids ↑ absorption of non-enteric coated ddI (Videx®) buffer; take pediatric solution with antacids to ↑
absorption
Administer dapsone 2 hrs before non-enteric coated
Dapsone ↓ absorption of dapsone
ddI
Administer DLV 1 hr before or after non-enteric
Delavirdine ↓ DLV levels by 22% and ↓ ddI levels by 20%
coated ddI (Videx®) or change patient to Videx EC®
Administer fluoroquinolone at least 2 hrs before or 6
Fluoroquinolones ↓ fluoroquinolone absorption hrs after non-enteric coated ddI (Videx®) or change
patient to Videx EC®
Oral formulation contains magnesium stearate and
Administer oral ganciclovir 2 hrs before ddI. Monitor
Ganciclovir can ↑ ddI levels by up to 80% and ddI ↓ oral
for ddl toxicity
ganciclovir levels by up to 20%
Administer ketoconazole 2 hrs before non-enteric
Ketoconazole ↓ absorption of ketoconazole
coated ddI
Administer Indinavir 1 hr before or 2 hrs after non-
Indinavir ↓ absorption of IDV
enteric coated ddI
Administer 2 hrs before non-enteric coated ddI
Itraconazole ↓ absorption of itraconazole
(Videx®) or change patient to Videx EC®
Neurotoxins such as cisplatin, dapsone,
ethionamide, isoniazid, metronidazole,
Monitor for toxicity; decrease dose or switch to
Neurotoxins nitrofurantoin, pentamidine (iv), phenytoin,
alternative agent if neuropathy intolerable
vincristine, and zalcitabine may exacerbate or ↑ risk
of peripheral neuropathy
Zalcitabine: Do not use together
Agents such as alcohol, pentamidine (iv), stavudine,
Pancreatoxins Pentamidine: Suspend ddI therapy during treatment
valproic acid, zalcitabine may ↑ risk of pancreatitis
with IV pentamidine
May ↓ ddI absorption; although one study suggests Separate dosing of non-enteric coated ddI and
Ritonavir
not significant (↓ levels by 13%) ritonavir by 2.5 hrs
Tenofovir ↑ didanosine levels Take Tenofovir 2 hrs before or 1 hr after ddI
Administer tetracyclines 4 hrs before or after non-
Tetracyclines ↓ tetracycline absorption
enteric coated ddI

EPIVIR® (LAMIVUDINE, 3TC)

Inhibits: none
Induces: none
Undergoes mainly renal elimination
CONCOMITANT DRUG INTERACTION HOW TO MANAGE INTERACTION
TMP/SMX ↑ lamivudine levels by 44% Monitor for toxicity

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72 CHAPTER 7 – ANTIRETROVIRAL DRUG INTERACTIONS

ZERIT ® (STAVUDINE, d4T)

Inhibits: none
Induces: none
Undergoes mainly renal elimination
CONCOMITANT DRUG INTERACTION HOW TO MANAGE INTERACTION
Neurotoxins such as cisplatin, dapsone, didanosine,
ethionamide, isoniazid, metronidazole, Evaluate on a case by case by case basis; use
Neurotoxins nitrofurantoin, pentamidine (iv), phenytoin, alternative agent if possible: monitor for toxicity if
vincristine, and zalcitabine may exacerbate or ↑ risk used together
of peripheral neuropathy
Didanosine May ↑ risk of pancreatitis Monitor for toxicity
Probenicid May inhibit tubular secretion of stavudine Monitor for toxicity
Zidovudine May ↓ antiviral activity Do not use together

HIVID ® (ZALCITABINE, ddC)

Inhibits: none
Induces: none
Undergoes mainly renal elimination
CONCOMITANT DRUG INTERACTION HOW TO MANAGE INTERACTION
May ↑ ddC levels and increase risk of peripheral
Aminoglycosides Monitor for toxicity
neuropathy
May ↑ ddC levels and increase risk of peripheral
Amphotericin B Monitor for toxicity
neuropathy
Antacids ↓ ddC levels by 25% Separate dosing of zalcitabine from antacids
Cimetidine ↓ ddC clearance Monitor for toxicity
May ↑ ddC levels and ↑ risk of peripheral
Foscarnet Monitor for toxicity
neuropathy
Neurotoxins such as cisplatin, dapsone, didanosine, Evaluate on a case by case by case basis; use
disulfiram, ethionamide, gold, hydralazine, alternative agent if possible: monitor for toxicity if
iodoquinol, isoniazid, metronidazole, nitrofurantoin, used together
Neurotoxins
pentamidine (iv), phenytoin, vincristine, and Didanosine: do not use together
stavudine may exacerbate or ↑ risk of peripheral Pentamidine: Suspend ddC throughout and for 1
neuropathy week after IV pentamidine
Didanosine: Do not use together
Pancreatoxins such as alcohol, didanosine
Pancreatoxins Pentamidine: Suspend ddC throughout and for 1
pentamidine, valproic acid may ↑ risk of pancreatitis
week after IV pentamidine
Probenecid ↑ ddC levels by 50% If necessary to use together, monitor for ddC toxicity
Trimethoprim ↑ ddC AUC by 37% Monitor for toxicity
Monitor for toxicity; avoid combination in patients
Zidovudine May ↑ risk of pancreatitis
with a history of or other risk factors for pancreatitis

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 CHAPTER 7 – ANTIRETROVIRAL DRUG INTERACTIONS 73

RETROVIR® (ZIDOVUDINE, ZDV, AZT)

Inhibits: none
Induces: none
Metabolized by glucuronyl transferase
CONCOMITANT DRUG INTERACTION HOW TO MANAGE INTERACTION
Amphotericin B May ↑ risk of bone marrow toxicity Monitor for toxicity; CBC weekly
Evaluate concomitant use on a case by case basis;
Certain antineoplastics may ↑ risk of bone marrow
Anti-neoplastics monitor for toxicity if used with a myelosuppressive
toxicity
chemotherapeutic agent
Not expected to produce clinically significant events;
Atovaquone ↑ AZT AUC by 35%
monitor for AZT toxicity
Clarithromycin ↓ AZT AUC by 25% No dosage adjustments recommended
Dapsone May ↑ risk of bone marrow toxicity Monitor for toxicity
↑ AZT AUC by 74% through inhibition of
Fluconazole Monitor for AZT toxicity
glucuronidation
Flucytosine May ↑ risk of bone marrow toxicity Monitor for toxicity
Foscarnet May ↑ risk of bone marrow toxicity Monitor for toxicity
If combination must be used, may need to reduce
dose or discontinue one or both agents to minimize
Ganciclovir May ↑ risk of bone marrow toxicity
bone marrow toxicity; CBC with diff 3 x/week initially
then weekly
If combination must be used, may need to reduce
Interferon-alpha May ↑ risk of bone marrow toxicity dose or discontinue one or both agents to minimize
bone marrow toxicity
No dosage adjustments recommended; monitor for
Methadone ↑ AZT AUC by 50% in 4/9 patients studied
toxicity
Pentamidine May increase risk of bone marrow toxicity Monitor for toxicity
Phenytoin May ↓ AZT clearance No data on dosage adjustments
Probenecid Can ↑ AZT levels Monitor for AZT toxicity
Pyrimethamine May ↑ risk of bone marrow toxicity Monitor for toxicity
Ribavirin ↓ antiviral activity in vitro Avoid combination
Stavudine (d4T) May ↓ antiviral activity Do not use together
May ↑ risk of anemia and neutropenia. ↑ AZT levels
TMP/SMX CBC with diff weekly; monitor for toxicity
and decrease AZT clearance (high dose TMP/SMX)
Valproic Acid ↑ AZT AUC by 79% Monitor for AZT toxicity

VIREAD ® (TENOFOVIR)
Inhibits: none
Induces: none
Undergoes mainly renal elimination
CONCOMITANT DRUG INTERACTION HOW TO MANAGE INTERACTION
Take tenofovir 2 hrs before or 1 hr after noninteric-
Didanosine ↑ absorption of ddI (noninteric coated Videx ) ®
coated ddI or use Videx EC®

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 74
Table 3 – Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Drug Interactions
CONCOMITANT DRUG MECHANISM OF INTERACTION RESCRIPTOR (DELAVIRDINE, DLV) SUSTIVA (EFAVIRENZ, EFV) VIRAMUNE (NEVIRAPINE, NVP)
↓ DLV AUC 41%
Interferes with absorption of some
Antacids Administer antacids 1 hr before or No interaction No interaction
NNRTIs
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NNRTIs may affect levels of certain
Antiarrhythmics
antiarrhythmics
Carbamazepine, phenytoin,
phenobarbital, and primidone may
Anticonvulsants significantly ↓ NNRTI levels;
NNRTIs may ↑ or ↓ levels of certain
anticonvulsants
Itraconazole, fluconazole,
after DLV
DLV may ↑, EFV may ↑ or ↓, and NVP may ↓ levels of antiarrhythmics metabolized by the CYP 3A4 system (i.e.
quinidine). Use with caution, no data on dosage adjustments
Carbamazepine, fosphenytoin, phenytoin, phenobarbital, and primidone may significantly ↓ NNRTI levels; DLV may ↑
levels of carbamazepine, ethosuximide, fosphenytoin, phenytoin, tiagabine, and zonisamide; EFV may ↑ or ↓ levels of
carbamazepine, ethosuximide, tiagabine, and zonisamide; NVP may ↓ levels of carbamazepine, ethosuximide,
lamotrigine, tiagabine, valproic acid, and zonisamide. Use with caution and monitor closely or consider alternative
anticonvulsant that is less likely to interact [i.e. gabapentin, levetiracetam, oxcarbazepine, topiramate, (lamotrigine and
valproic acid also options with DLV and EFV)].

CHAPTER 7 – ANTIRETROVIRAL DRUG INTERACTIONS

No dosage adjustments necessary
ketoconazole, and voriconazole NVP can ↓ ketoconazole AUC up to
Antifungals No data when given with fluconazole; no data
may ↑ NNRTI levels; NVP may ↓ 60%; use alternative azole antifungal
with other azoles
antifungal levels
EFV and DLV can ↑ levels of
Antihistamines astemizole and terfenadine Use alternative antihistamine such as loratidine, cetirizine or fexofenadine (astemizole and terfenadine removed from
(non-sedating) increasing risk of life-threatening US market)
arrhythmias
ANTIMYCOBACTERIALS
May affect levels of etoposide,
Antineoplastics DLV may ↑ levels of these agents, EFV may ↑ or ↓ levels; NVP may ↓ levels. No data on dosage adjustment
paclitaxel, vinblastine
May affect levels of alprazolam,
DLV may ↑, EFV may ↑ or ↓ and NVP may ↓ levels of BZDs listed. Consider alternative agent such as lorazepam,
Benzodiazepines clonazepam, diazepam, estazolam,
oxazepam, temazepam, zolpidem
flurazepam, midazolam, triazolam
EFV may ↑ or ↓ CCB levels; DLV
Calcium Channel
may ↑ CCB levels; NVP may ↓ CCB Use with caution; dosage adjustment may be necessary
Blockers
levels
DLV and EFV may ↑ cisapride
Cisapride levels increasing risk of life- Do not use together (cisapride now available on a compassionate use basis only)
threatening arrhythmias
Administer DLV 1 hour before or 1
Buffers in non-enteric-tablets may ↓
Didanosine hour after Videx or consider Videx No interaction No interaction
absorption of DLV
EC
Clarithromycin can ↑ levels of Clarithromycin levels ↑ 100%; DLV Clarithromycin levels ↓ 39%; NVP levels ↑ 26%, clarithromycin
Clarithromycin NNRTIs; NNRTIs can ↑ or ↓ levels levels ↑ 44%. Dose reduce alternative recommended or levels ↓ 30%; No data on dosage
of clarithromycin clarithromycin in renal failure consider dosage adjustment adjustment
DLV and EFV may ↑ ergot levels
Ergot Alkaloids leading to toxicity; NVP may ↓ ergot Do not use together Do not use together No data
levels
Do not use lovastatin or simvastatin with DLV or EFV, use lower doses of
DLV or EFV may ↑ statin levels
HMG-CoA Reductase other statins with caution; pravastatin least likely to interact, fluvastatin also
leading to toxicity; NVP may ↓ No data
Inhibitors (“statins”) not likely to interact with EFV (metabolized by CYP 2C9 which DLV can
levels of some statins
inhibit)
 Table 3 – Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Drug Interactions
CONCOMITANT DRUG MECHANISM OF INTERACTION RESCRIPTOR (DELAVIRDINE, DLV) SUSTIVA (EFAVIRENZ, EFV) VIRAMUNE (NEVIRAPINE, NVP)
NNRTIs may affect levels of some DLV may ↑ levels of cyclosporine, sirolimus, and tacrolimus; EFV may ↑ or ↓ levels of these agents; NVP may ↓ levels
Immunosuppressants
immunosuppressants of these agents. Monitor immunosuppressant levels closely
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Some NNRTIs may ↓ methadone
Methadone
levels
May ↑ or ↓ levels of nefazadone;
Nefazadone nefazadone may ↑ levels of
efavirenz
DLV and EFV may ↑ levels of
Oral Contraceptives estrogen-containing OCs; NVP may
↓ levels of estrogen-containing OCs
EFV may ↓ rifabutin levels while
May ↓ methadone levels; titrate dose
No data
as necessary
No data, use with caution
No dosage adjustment ↑ ethinyl estradiol levels 37%; no
recommended dosage adjustment recommended
Dose: May consider rifabutin 450-
May ↓ methadone levels; titrate dose
as necessary
↓ ethinyl estradiol levels 20%
Recommend alternative method for
contraception
No significant interaction based on

CHAPTER 7 – ANTIRETROVIRAL DRUG INTERACTIONS

Rifabutin DLV can ↑ rifabutin levels; rifabutin Do not use together 600 mg po qd with standard dose PK studies; usual doses of each (No
can ↓ DLV levels EFV (no clinical data) clinical data)
↓ EFV AUC 26%
Rifampin can significantly ↓ NNRTI Rifampin may ↓ NVP levels; avoid
Rifampin
levels
Do not use together Dose: Consider ↑ EFV to 800 mg po combination if possible
qhs
PIs See Table 8 in Chapter 6, Antiretroviral Therapy, on recommended dosage adjustments for PI/NNRTI combinations
DLV may ↑ levels of citalopram and
Selective Serotonin May affect levels of citalopram and sertraline; fluoxetine, fluvoxamine May ↓ levels of citalopram and
Use with caution or use alternative
Reuptake Inhibitors sertraline; fluoxetine, fluvoxamine may ↑ levels of DLV; Use caution or antidepressant such as paroxetine
sertraline; no data, consider
(SSRIs) may ↑ NNRTI levels consider alternative SSRI such as paroxetine
paroxetine
Based on interaction with IDV, St.
St. John’s Wort John’s Wort may induce CYP 3A4 No data available; avoid concomitant use
and ↓ NNRTI levels
Tamoxifen NNRTIs may ↑ or ↓ tamoxifen levels No data on dosage adjustment ; monitor for toxicity.
DLV may ↑ warfarin levels, EFV
Warfarin may ↑ or ↓ warfarin levels and NVP Monitor INR closely and adjust warfarin dose as needed
may ↓ warfarin levels

75
 76
Table 4 – Protease Inhibitor (PI) Drug Interactions
AGENERASE KALETRA
MECHANISM OF CRIXIVAN VIRACEPT NORVIR FORTOVASE/INVIRASE
CONCOMITANT DRUG (AMPRENAVIR, (LOPINAVIR/RITONAVIR
INTERACTION (INDINAVIR, IDV) (NELFINAVIR, NFV) (RITONAVIR, RTV) (SAQUINAVIR, SQV)
APV) KAL)
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May ↑ risk of
Alcohol kidney stones;
instruct patient to
avoid alcohol use
PIs may increase levels
Antiarrhythmics of certain Do not use amiodarone, flecainide, propafenone, or quinidine with Norvir  or Kaletra; use with caution with other PIs
antiarrhythmics
Carbamazepine,
Carbamazepine, fosphenytoin, phenytoin, phenobarbital, and primidone may ↓ PI levels; PIs may ↑ levels of carbamazepine,
fosphenytoin, phenytoin,
phenobarbital, and ethosuximide, tiagabine, and zonisamide; RTV and KAL can also ↑ levels of fosphenytoin and phenytoin and ↓ levels of lamotrigine

CHAPTER 7 – ANTIRETROVIRAL DRUG INTERACTIONS

Anticonvulsants (38). Avoid concomitant use of carbamazepine, fosphenytoin, phenytoin, phenobarbital, and primidone with PIs (carbamazepine
primidone may ↓ PI
markedly ↓ IDV levels). Consider alternative anticonvulsant that is less likely to interact such as gabapentin, levetiracetam,
levels, PIs can ↑ levels
oxcarbazepine, topiramate, valproic acid
of some anticonvulsants
Azole antifungals Itraconazole doses >
(itraconazole, Consider 200 mg qd not
Ketoconazole
decreasing dose of NFV levels ↑ 35%, SQV levels ↑ 3-fold
ketoconazole, levels ↑ 3, do not recommended;
IDV to 600 mg po no dosage with ketoconazole; no
Antifungals (Azoles) fluconazole, No data exceed 200 mg Ketoconazole AUC ↑
q8h with adjustments data on dosage
voriconazole) can ↑ of ketoconazole 3-fold; Ketoconazole
ketoconazole or recommended adjustments
levels of PIs, PIs can ↑ daily doses > 200 mg qd
itraconazole
levels of azoles not recommended
PIs ↑ levels of
Antihistamines astemizole and Use alternative non-sedating antihistamine such as cetirizine, fexofenadine, loratidine
terfenadine increasing
(non-sedating) (astemizole and terfenadine removed from US market)
risk of life-threatening
arrhythmias
ANTIMYCOBACTERIALS
May ↑ levels of
Antineoplastics docetaxel, paclitaxel, No data; Monitor for toxicity.
vinblastine, vincristine,
vinerelbine
All PIs may ↑ levels of
alprazolam, diazepam, Contraindicated/do not use together: midazolam, triazolam; use with caution: alprazolam, clonazepam, diazepam, flurazepam; levels
Benzodiazepines clonazepam, not likely to be affected: lorazepam, oxazepam, temazepam, zolpidem (RTV and KAL may ↑ zolpidem levels)
flurazepam, midazolam,
triazolam
Calcium Channel May ↑ levels of some Do not use together: bepiridil (contraindicated with amprenavir and ritonavir; should be avoided with other PIs if possible); use with
Blockers CCBs caution: Amlodipine, diltiazem, felodipine, isradipine, nicardipine nifedipine, nimodipine, nisoldipine, nitrendipine, verapamil
May ↑ levels of cisapride
Cisapride causing life-threatening Do not use together (cisapride now available on a compassionate use basis only)
arrhythmias
PIs may significantly ↑ APV AUC ↑ 18%; Clarithromycin Clarithromycin Clarithromycin levels ↑ Reduce dose of
Clarithromycin clarithromycin levels; No dosage AUC ↑ 53%; No No data levels ↑ 77%; 45%, SQV levels ↑ clarithromycin in
clarithromycin may ↑ PI adjustment dosage adjustment Reduce dose in 177%; No data on patients with renal
 Table 4 – Protease Inhibitor (PI) Drug Interactions
AGENERASE KALETRA
MECHANISM OF CRIXIVAN VIRACEPT NORVIR FORTOVASE/INVIRASE
CONCOMITANT DRUG (AMPRENAVIR, (LOPINAVIR/RITONAVIR
INTERACTION (INDINAVIR, IDV) (NELFINAVIR, NFV) (RITONAVIR, RTV) (SAQUINAVIR, SQV)
APV) KAL)
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levels recommended recommended patients with dosage adjustment insufficiency

renal
insufficiency
Clozapine May ↑ clozapine levels Do not use with RTV or KAL; Use with caution with other PIs
Dalfopristin;
May ↑ PI levels Monitor for toxicity
quinupristin (Synercid)
Administer
Administer IDV 1
Non-enteric coated Videx 1 hr Administer Videx 1 hr
Interaction not hr before or 1 hr Interaction not
Didanosine (Videx) tablets may ↓ absorption before or 2 hrs Interaction not likely before or 2 hrs after
likely after Videx or use likely

CHAPTER 7 – ANTIRETROVIRAL DRUG INTERACTIONS

of some PIs after RTV or use KAL or use Videx EC
Videx EC
Videx EC
Propylene glycol in APV
liquid and alcohol in Do not use with Do not use with Do not use with KAL
Disulfiram
RTV and KAL liquid APV liquid RTV liquid liquid
may↑ toxicity
May ↑ ergot levels
Ergot Alkaloids Do not use together
leading to toxicity
Levels of PI and
Erythromycin Monitor for toxicity or use alternative such as azithromycin
erythromycin may ↑
Grapefruit Juice ↓ IDV levels 26%; no data with other PIs; avoid concomitant use
PIs may ↑ levels of Contraindicated/do not use together: lovastatin, simvastatin; use low dose with caution: atorvastatin, cerivastatin (removed from US
HMG-CoA Reductase
certain HMG-CoA
Inhibitors market); levels not likely affected: fluvastatin, pravastatin (RTV and KAL may ↓ fluvastatin levels)
reductase inhibitors
PIs may ↑ levels of
Immunosuppressants cyclosporine, sirolimus, Monitor immunosuppressant levels closely
tacrolimus
Methadone
May ↓ methadone ↓ methadone AUC
PIs may ↓ methadone No effect on levels ↓ 37%;
Methadone No data levels; titrate dose No data 53%; titrate dose if
levels methadone levels titrate dose if
if needed needed
needed
Avoid
RTV and KAL liquids
concomitant
contain alcohol, may Avoid concomitant
Metronidazole Metronidazole
cause disulfiram-like alcohol with KAL liquid
with RTV liquid
reaction
and KAL liquid
PIs may ↑ levels of
Nefazadone;
Nefazadone Start with low dose; titrate slowly and monitor for toxicity
Nefazadone may ↑ PI
levels
PIs may ↑ levels of
Neuroleptics Do not use clozapine or pimozide with RTV or KAL
neuroleptics

77
 78
Table 4 – Protease Inhibitor (PI) Drug Interactions
AGENERASE KALETRA
MECHANISM OF CRIXIVAN VIRACEPT NORVIR FORTOVASE/INVIRASE
CONCOMITANT DRUG (AMPRENAVIR, (LOPINAVIR/RITONAVIR
INTERACTION (INDINAVIR, IDV) (NELFINAVIR, NFV) (RITONAVIR, RTV) (SAQUINAVIR, SQV)
APV) KAL)
HIV/AIDS PRIMARY CARE GUIDE, FLORIDA AIDS EDUCATION AND TRAINING CENTER, UNIVERSITY OF FLOIRDA, 2002

↑ rifabutin AUC by
↑ rifabutin by 207% and ↓ NFV ↑ rifabutin levels; ↓
204% and ↓ IDV AUC by 32% ↑ rifabutin Cmax 2-fold,
↑ rifabutin AUC ↑ rifabutin levels SQV AUC 43%
PIs can significantly ↑ levels by 32% Dose: ↓ rifabutin to AUC 3-fold, and Cmin
193% 4-fold Dose: ↓ rifabutin to
Rifabutin rifabutin levels; rifabutin Dose: ↑ IDV to 150 mg po qd, 5-fold
Dose:↓ rifabutin Dose: ↓ rifabutin 150 mg po qd (Use
may ↓ some PI levels 1000 mg po q8h; ↓ consider ↑ NFV to Dose: ↓ dose to 150
to 150 mg po qd to 150 mg po qod Fortovase formulation
rifabutin 50% (150 1000 mg po tid mg po qod
only)
mg po qd) (when using 750
mg po tid regimen)

CHAPTER 7 – ANTIRETROVIRAL DRUG INTERACTIONS

↓ RTV levels by
↓ APV Cmin by ↓ IDV AUC by ↓ NFV AUC by
Rifampin can 35%; No data on ↓ SQV AUC 80%; Do ↓ Iopinavir AUC 75%
Rifampin 92%; Do not use 89%; Do not use 82%; Do not use
significantly ↓ PI levels dosage not use together Do not use together
together together together
adjustment
NNRTIs See table on recommended dosage adjustments for PI/NNRTI combinations
↓ norethindrone
↓ ethinyl
levels 18%, ↓ ↓ ethinyl estradiol
↑ ethinyl estradiol estradiol levels
Certain PIs may ↓ oral ethinyl estradiol levels by 40-60%;
levels 24%; no 40%;
Oral Contraceptives No data levels 47%; No data recommend barrier
contraceptive levels dosage adjustment recommend
recommend barrier method of
recommended barrier method of
method of contraception
contraception
contraception
Pimozide Do not use together
PIs See Table 9 in Chapter 6, Antiretroviral Therapy, for Recommended Dosage Adjustments for Dual PI Combinations
Selective Serotonin
Reuptake Inhibitors Use with caution or use alternative anti-depressant (interaction less likely with paroxetine)
(SSRIs)
PIs may ↑ sildenafil
Sildenafil Dose: max sildenafil 25 mg in 48 hrs (based on recommendations for ritonavir)
levels leading to toxicity
Data indicates that St. Johns’ Wort may ↓ levels of IDV, no data with other PIs. Instruct patient to avoid concomitant use of St. Johns’
St. John’s Wort May ↓ levels of PIs
Wort with PIs
Tamoxifen May ↑ tamoxifen levels Monitor for toxicity
Since KAL contains
↓ theo levels
RTV, may ↓ theo
Theophylline 47%; monitor
levels; monitor levels
levels closely
closely
Some PIs may ↑ TCA Use alternative Use alternative
Tricyclic Interaction not Interaction not Interaction not
levels (metabolized by antidepressant or Interaction not likely antidepressant or use
Antidepressants likely likely likely
CYP2D6) use with caution with caution
Venlafaxine May ↓ levels of PIs No data ↓ IDV levels; do not use together; No data with other PIs
PIs may ↑ warfarin
Warfarin Monitor warfarin levels closely
levels
 CHAPTER 7 – ANTIRETROVIRAL DRUG INTERACTIONS 79

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HIV/AIDS PRIMARY CARE GUIDE, FLORIDA AIDS EDUCATION AND TRAINING CENTER, UNIVERSITY OF FLOIRDA, 2002
82 CHAPTER 7 – ANTIRETROVIRAL DRUG INTERACTIONS

HIV/AIDS PRIMARY CARE GUIDE, FLORIDA AIDS EDUCATION AND TRAINING CENTER, UNIVERSITY OF FLOIRDA, 2002