Protease
Inhibitor Drug Interactions
by Evelyn Rose, PharmD, and Mary Romeyn, MD
Recent advances in HIV treatment have brought new hope to
many people living with HIV. Often, a new treatment advance
is accompanied by new challenges that may sometimes seem
overwhelming. The protease inhibitor drugs, in particular,
exact a price for all the promise that they offer.
While much has been written about the potential side effects
of protease inhibitors and the need to adhere to a strict
schedule in order for them to work most effectively, less
attention has been paid to the potential for interactions
between this class of drugs and other drugs, or even between
different members of the class. Combining drugs is rarely
simple in the age of protease inhibitors. Every change in
a regimen must take into account the potential for each
new drug to change the behavior or concentration of a drug
already being used. Each new medicine must be carefully
evaluated for safety in the presence of other drugs already
being taken. Understanding some of the concepts of drug
interactions and their potential for adverse effects can
help people avoid danger.
Overview of Drug Metabolism
Drugs taken by mouth pass through the stomach to the small
intestine, where they are absorbed into the bloodstream
and carried to their site of action. Intravenous drugs are
placed directly into the bloodstream. Drugs injected into
muscle (intramuscular), under the skin (subcutaneous) or
allowed to diffuse through the skin (transdermal) make their
way to the bloodstream more slowly through the soft tissues
of the body.
Once in the body, many drugs are broken down into other compounds
in stages before they are excreted. These other compounds
are called metabolites. The chemical structure of a drug
and its metabolites helps determine how quickly, in what
way and by what route the body will get rid of them. Furthermore,
people’s bodies are unique and clear drugs at different
rates and levels of efficiency.
To estimate the concentration of a drug in the bloodstream
and the length of time it will be active, it is necessary
to consider how much is taken (the dose), how often it is
taken (the schedule), and in what way and how quickly a
drug will be excreted. Understanding these factors helps
determine how much of a drug is needed and how often it
must be taken to maintain a therapeutic level.
The liver breaks down most chemicals and natural waste products
in the body. These products are then carried by the blood
to the kidneys to be washed out. The kidneys may also clear
from the bloodstream directly other drugs which do not need
to be broken down by the liver. Medicines that affect the
function of either the liver or the kidneys may alter their
ability to clear drugs and metabolites. If a drug continues
to be taken and its removal from the body has been reduced
or blocked, drug levels can rise until they reach toxic
(poisonous) levels. If drug elimination has been accelerated,
drug concentrations can fall below effective levels.
The Cytochrome P450 System
An important part of the body’s disposal mechanism is
the cytochrome P450 (CP450) system. CP450 is a collection
of enzymes that drive chemical reactions or changes. Most
of these enzymes are in the liver. Different enzymes or
groups of enzymes break down different drugs. Some people’s
enzymes are extremely efficient, while others’ enzymes
work less well or more slowly. Thus, differences in people’s
abilities to break down or metabolize drugs will directly
affect the length of time that a drug remains in the body,
as well as its blood level. Broiled foods, cigarettes and
certain vegetables also affect metabolism. Some drugs have
very potent effects on these enzymes, and may substantially
alter drug effects and toxicities (see “Metabolism”
below).
Types of Drug Interactions
Drugs can affect one another by acting at any step between
intake and excretion.
1.
Absorption
If one drug changes the rate at which other drugs move from
the stomach to the small intestine, their rate of absorption
into the blood will be affected. If one drug changes the
level of acidity in the stomach, absorption of other drugs
may change. If one drug binds to another, neither may be
absorbed at all.
2.
Distribution
A proportion of some drugs binds to blood proteins. If there
are too few binding proteins, or if other drugs have already
bound to these proteins, there will be more active drug
in the body and drug performance will be changed.
3.
Metabolism
Many drugs, including protease inhibitors, are excreted through
the CP450 system. Other drugs stimulate or speed up the
action of the CP450 system. If the activity of an enzyme
is decreased, drugs requiring that enzyme for metabolism
will have increased blood concentrations, effects and toxicities.
If, instead, enzyme activity is revved up by one drug, other
drugs may be broken down faster and levels may drop too
low.
4.
Elimination
Some drugs can alter the way the kidneys remove chemicals
from the body. They may also affect the efficiency of the
kidneys, particularly their ability to control the concentration
of drug being eliminated. Other drugs may be directly toxic
to the kidneys, reducing their function and resulting in
higher levels of drugs.
5.
Other types of drug interactions
Drug effects can be additive (effect + effect = double effect);
synergistic (effect + effect = more than double effect);
or antagonistic (effect vs effect = less than double effect).
Interactions may result from the direct action of a drug
or an indirect action several steps removed. Drug interactions
may also affect laboratory values used to judge the performance
of other drugs. Any of these types of interactions can lead
to unplanned and potentially damaging results called adverse
drug events.
Protease Inhibitor Drug Interactions
Much is already known about protease inhibitors and the ways
they affect and are affected by other drugs. However, much
is still unknown. Table 1 (see note at beginning of
article) provides a summary of currently recognized
drug interactions.
Within the CP450 system, the enzyme most affected by protease
inhibitors is CYP3A. Ritonavir (Norvir) is the most frequent
inhibitor of this enzyme, while indinavir (Crixivan) and
nelfinavir (Viracept) have fewer effects on CYP34, and saquinavir
(Invirase) affects it even less. The protease inhibitors
also use the CP450 system for their own metabolism. Therefore,
other drugs can affect the blood concentrations of protease
inhibitors as well.
Animal studies suggest that protease inhibitors currently
in development—141W94 (Glaxo Wellcome/Vertex), ABT-378
(Abbott Laboratories) and KNI-272—may cause fewer drug
interactions due to CP450 inhibition. However, human studies
have not been completed.
Potential protease inhibitor adverse drug events include
nausea, vomiting, diarrhea, taste changes, peripheral neuropathy
and mild to significant liver damage. These adverse effects
may occur more frequently with increased blood concentrations
of protease inhibitors. Indinavir, when present in too high
a concentration, can crystallize in the kidneys and form
kidney stones. Saquinavir may cause mouth sores. Adverse
drug events of other various drug classes discussed in this
article are listed in the table on pages 33-38 (see
note at beginning of article).
Important potential interactions of protease inhibitors with
other drug classes are described below. Little study has
been done regarding the interactions between protease inhibitors
and illegal or recreational drugs, and they are not the
focus of this article (see BETA, March 1997, page 5).
Antialcohol
Drugs
Disulfiram (Antabuse) is used to help people stop drinking
alcohol. If the drug is taken with alcohol, intense flushing
and abdominal pain can result. Metronidazole (Flagyl) may
have a similar effect if taken with alcohol. Ritonavir contains
alcohol in both liquid and pill formulations, and should
not be used with these drugs.
Antianxiety
Drugs
The metabolism of most drugs of the benzodiazepine class,
including diazepam (Valium), is inhibited by protease inhibitors
and especially by ritonavir. The result may be oversedation
and risk of respiratory depression. Use of ritonavir with
most benzodiazepines and with zolpidem (Ambien) should be
avoided. On the other hand, Lorazepam (Ativan), oxazepam
(Serax) and temazepam (Restoril) can be used with ritonavir,
although they may require increased dosing.
Antiarrhythmics
Antiarrhythmic drugs are used to stabilize the heart rate.
Elimination of many of these drugs, including digoxin, can
be reduced when ritonavir is present in the body. Careful
monitoring of antiarrhythmic effects and blood levels is
essential.
Antiasthmatics
Levels of the antiasthmatic drug theophylline (Theo-Dur,
Uniphyl) can be lowered by ritonavir, so blood levels and
response to therapy should be monitored.
Antibiotics
The antibiotics erythromycin and clarithromycin (Biaxin)
may have increased serum levels when taken with ritonavir,
nelfinavir or saquinavir. This is usually not a worrisome
interaction, except in people who also have reduced kidney
function. In such cases, the dose of clarithromycin should
be decreased by 50-75%. Azithromycin (Zithromax) is less
likely to interact with protease inhibitors. Metronidazole
is discussed above.
Anticancer
Agents
The blood levels of some anticancer drugs may be increased
in people who take ritonavir. Because of the serious and
sometimes irreversible toxicities to the blood, gastrointestinal
tract and central nervous system caused by most anticancer
drugs, it is probably best to avoid ritonavir and use another
protease inhibitor instead.
Anticoagulants
Warfarin (Coumadin) levels are unpredictable when used with
ritonavir, and side effects or loss of warfarin effect should
be closely monitored.
Antidepressants
Tricyclic antidepressants (TCA), such as amitriptyline (Elavil),
desipramine (Norpramin) and nortriptyline (Pamelor), can
build up to dangerous levels when used with ritonavir and
should be taken at reduced doses. Blood levels of selective
serotonin reuptake inhibitors (SSRI), including fluoxetine
(Prozac), paroxetine (Paxil) and sertraline (Zoloft), can
also increase when taken with with ritonavir. Since TCA
are sometimes used to treat peripheral neuropathy or headaches,
and since both TCA and SSRI are sometimes used together
to treat depression, close monitoring for side effects is
recommended. Bupropion (Wellbutrin) should not be taken
with ritonavir at all, since increased concentrations of
this drug can lead to seizures. Ritonavir taken with trazodone
(Desyrel), venlafaxine (Effexor) or nefazodone (Serzone)
can possibly result in dangerous cardiac side effects.
Antidiabetic
Drugs
Because ritonavir may block the breakdown of some antidiabetic
drugs such as glyburide (Diabeta, Micronase) and glipizide
(Glucotrol), the risk of developing seriously low blood
sugar is significant. Careful daily testing of fasting blood
sugar, together with close medical monitoring and follow-up,
are needed. Newer agents such as metformin (Glucophage)
and acarbose (Precose) are not broken down in the liver
and no drug interactions have been reported to date. Troglitazone
(Rizulin) is extensively broken down by the liver. Even
though interactions with protease inhibitors have not yet
been reported, combined use should probably proceed with
caution.
Antidiarrheals
Diphenoxylate (Lomotil) and loperamide (Imodium) may be less
effective when taken with ritonavir, causing a worsening
of diarrhea symptoms. Increased dosages or the addition
of another antidiarrheal medicine may be necessary.
Antifungals
Ketoconazole (Nizoral) and related drugs block the breakdown
of saquinavir, indinavir and perhaps other protease inhibitors,
with a resulting increase in protease inhibitor levels.
Higher saquinavir levels may be more effective, so no dose
adjustment is needed. Due to the potential for increased
indinavir toxicity, dose reductions are recommended, especially
if used with ketoconazole. Fluconazole (Diflucan) may be
the best choice for use with protease inhibitors.
Antihistamines
Non-sedating antihistamines such as astemizole (Hismanal),
loratadine (Claritin) and terfenadine (Seldane) should not
be used with protease inhibitors, as their levels may increase.
Sudden death has been reported as a result of high blood
levels of these drugs. In addition, these antihistamines
may prolong the elimination of protease inhibitors from
the body. Treatment with cetirizine (Zyrtec) may be less
risky if a non-sedating antihistamine is required. Traditional
over-the-counter antihistamines may be used as usual.
Antihypertensives
There are so many drugs used to lower blood pressure that
to name them all would take up an entire article. Here they
will be discussed by drug class only. People receiving blood
pressure medications should discuss drug interactions with
their doctor.
Calcium channel blocker levels may be increased by any of
the protease inhibitors, but ritonavir increases these levels
the most. Ritonavir may increase both beta blocker and alpha
blocker levels. Losartan (Cozaar) levels may be either increased
or decreased by ritonavir. People should watch closely for
increased effects such as low blood pressure and other associated
signs of toxicity if they are taking any of these drugs.
Antimigraine
Drugs
Migraine is a specific type of headache that may be treated
by using blood vessel constrictors, or prevented by using
beta blockers or tricyclic antidepressants. The ergot preparation
dihydroergotamine (DHE-45) is an example of the former.
Use of ritonavir should be avoided with these medications.
Beta blocker and calcium channel blocker drug interactions
are discussed under “Antihypertensives” above.
Tricyclic antidepressant drug levels can be increased by
ritonavir. Sumatriptin (Imitrex) has no reported interactions.
Antinausea
Drugs
Cisapride (Propulsid) metabolism is decreased when taken
with any of the protease inhibitors, which may increase
the concentration of cisapride to dangerous levels. Sudden
death may result from using this drug with protease inhibitors.
Ondansetron (Zofran) levels may be increased when taken
with protease inhibitors also, so a lower dose may be required.
Prochlorperazine (Compazine) toxicity should be monitored
carefully if ritonavir is taken, as ritonavir may block
its metabolism.
Antiparasitics
Ritonavir may increase levels of quinine-based drugs. Atovaquone
(Mepron) levels may be increased or decreased by ritonavir.
Metronidazole should not be taken with ritonavir because
of its disulfiram-like effect.
Antiretrovirals
ddI (Videx) can impair indinavir absorption, and the two
drugs should be taken 1-2 hours apart. Ritonavir may increase
indinavir and nelfinavir levels, and especially saquinavir
levels (by up to 20 times). A study has shown that saquinavir
at reduced doses (400-600 mg twice a day) plus ritonavir
(400-600 mg twice a day) has potent anti-HIV activity. Nevirapine
(Viramune) may reduce concentrations of indinavir, nelfinavir,
saquinavir and, to a lesser degree, ritonavir. Delavirdine
(Rescriptor) may increase levels of all protease inhibitors.
When taken with delavirdine, indinavir levels have been
observed to increase by up to 208%. The clinical significance
of these interactions with delavirdine is not yet known.
Antiseizure
Medications
Drug interactions between protease inhibitors and antiseizure
medications can be quite complicated. Ritonavir may increase
blood levels of carbamazepine (Tegretol) and ethosuximide
(Zarontin). However, ritonavir may decrease blood levels
of lamotrigine (Lamictal), divalproex (Depakote) and valproic
acid (Depakene). The effect of ritonavir on blood levels
of phenytoin (Dilantin) and fosphenytoin (Cerebyx) can be
unpredictable, with either higher or lower levels occurring.
Indinavir may increase the blood concentrations of phenytoin
and phenobarbitol (Luminal). Conversely, carbamazepine and
ethosuxamide may increase nelfinavir levels. Phenytoin and
phenobarbitol may decrease saquinavir, ritonavir and indinavir
levels. The clinical significance of these increases and
decreases is unknown. Serum levels of antiseizure medications
should be closely monitored when used in combination with
protease inhibitors.
Antitubercular
Drugs
Rifampin and rifabutin (Mycobutin), drugs used to treat tuberculosis,
tend to decrease protease inhibitor levels. Indinavir may
be least affected by this interaction. Protease inhibitors
may also cause increased levels of rifampin and rifabutin,
potentially resulting in toxic side effects. The Centers
for Disease Control and Prevention (CDC) have suggested
that either protease inhibitors be stopped for the 2-6 months
that rifampin or rifabutin must be used, or that rifabutin
(not rifampin) be used with other antitubercular drugs along
with indinavir as the only protease inhibitor in this situation.
It is important to discuss any proposed changes in therapy
with a physician familiar with the treatment of tuberculosis
and HIV. Stopping a protease inhibitor may result in the
development of drug resistance and may preclude later use
of that drug.
Antiulcer
Drugs
Cimetidine (Tagamet) may inhibit saquinavir breakdown and
increase saquinavir levels. Ritonavir may increase cimetidine
levels and increase the risk of developing side effects.
Alterations in gastric acidity due to antiulcer medications
may affect the amount of protease inhibitor absorbed into
the body. Lansoprazole (Prevacid) and omeprazole (Prilosec)
levels may be increased or decreased by ritonavir.
Antivirals
Use of indinavir or ritonavir with drugs that impair kidney
function requires close monitoring to avoid additive kidney
toxicity. These drugs include, but are not limited to, acyclovir
(Zovirax), cidofovir (Vistide) and foscarnet (Foscavir).
Cholesterol-Lowering
Agents
Drugs that lower cholesterol may reach increased levels in
the presence of ritonavir. Reduced dosing of these drugs
should be considered when used with ritonavir.
Hormones
Birth control pills containing ethinyl estradiol may not
be as effective for contraception when taken with either
indinavir or ritonavir. Alternate means of contraception
should be used. Medroxyprogesterone (Provera) levels may
also be reduced.
Marijuana
Derivatives
Dronabinol (Marinol), a marijuana derivative used to relieve
nausea or increase appetite, may reach increased levels
in the presence of any protease inhibitor. Therefore, dose
adjustment of dronabinol may be necessary.
Nonsteroidal
Anti-Inflammatory Drugs
The nonsteroidal anti-inflammatory drug (NSAID) group includes
over-the-counter medicines like ibuprofen (Advil) as well
as prescription drugs. Ritonavir inhibits the breakdown
of these medicines, slowing their elimination and leading
to a risk of increased drug levels. Symptoms associated
with increased NSAID levels include nausea, abdominal pain
and possibly bleeding ulcers. Piroxicam (Feldene) is especially
affected, and should not be used with ritonavir.
Opiates
Ritonavir speeds up the breakdown of some opiates, resulting
in low drug levels and inadequate pain control. Other opiates
may have their levels increased, resulting in potential
oversedation, respiratory depression and shock with potential
respiratory failure and death. People who take this combination
of medicines should be closely monitored. Heroin and opium,
in particular, may rise to dangerous levels. Methadone is
broken down by an unknown CP450 system enzyme, and there
is concern about increased levels when taken with ritonavir.
Ritonavir should not be used with meperidine (Demerol) or
propoxyphene (Darvocet or Darvon). Seizures may result with
the use of meperidine, and increased incidence of death
has been reported when using propoxyphene with ritonavir.
Other
Psychiatric Medications
Traditional antipsychotic drugs like haloperidol (Haldol)
may require significant dose reduction when taken with ritonavir.
Clozapine (Clozaril) blood concentrations are significantly
increased by ritonavir, so the drugs should not be taken
together. Risperidone (Risperdal), a newer antipsychotic
drug, may be used with ritonavir, but may require dose adjustment.
Olanzapine (Zyprexa) is metabolized by the enzyme CYP1A2.
There have been no reported drug interactions with olanzapine
to date. However, since ritonavir has a weak effect on this
enzyme, monitoring for adverse drug events is necessary.
Indinavir, nelfinavir and saquinavir have not yet been shown
to affect these medications. Antiseizure drugs were discussed
above.
Steroids
Prednisone and dexamethasone (Decadron) levels may be increased
when taken with ritonavir. Patients should be carefully
monitored for increased steroid effects.
Stimulants
Elimination of dexfenfluramine (Redux), methamphetamine (Desoxyn)
and methylphenidate (Ritalin) may be altered by ritonavir.
The resulting stimulant levels may be higher and therefore
more dangerous (e.g., dexfenfluramine), they may be lower
(e.g., methamphetamine) or they may be variable (e.g., methylphenidate).
Ritonavir should not be used with dexfenfluramine. Ritonavir
may also decrease caffeine levels. Nicotine may speed up
ritonavir elimination, reducing drug levels and increasing
the risk of drug resistance.
Avoiding Protease Inhibitor Interactions
The best way to avoid adverse drug effects resulting from
drug interactions is to learn as much as possible about
drugs being used. Pharmacists, doctors and nurses can be
good resources. People with HIV who take the time to learn
about this important aspect of their care can also teach
their healthcare providers.
Patients should carry a list of all their medications—including
dosages—and give this to every doctor, dentist, nurse
or pharmacist involved in their care. When possible, all
medications should be purchased from the same source. When
prescriptions come from more than one doctor, at least one
primary physician should be kept abreast of the overall
treatment regimen and all proposed changes in treatment.
Never adjust doses of medicines without first consulting
a physician.
Conclusion
Drug information is a powerful tool for maintaining and improving
quality of life when multiple medications are required.
Management of the drug interactions that accompany the use
of protease inhibitor drugs requires great attention to
detail. New drugs in development will expand the possibilities
for adverse drug events. A growing consensus on the need
for highly aggressive anti-HIV therapy increases the challenge
of avoiding adverse drug events. Healthcare providers experienced
in HIV care, or willing to research each potential drug
interaction, can provide essential information. People living
with HIV can educate themselves and thus be active players
in their health care.
Evelyn Rose, PharmD, is Clinical Pharmacist for Psychiatry,
and Pharmacy Quality Improvement Coordinator at Saint Francis
Memorial Hospital in San Francisco.
Mary Romeyn, MD, is Medical Director of the Andrew Ziegler
Foundation, a member of the San Francisco AIDS Foundation’s
Scientific Advisory Committee and author of Nutrition and
HIV: A New Model for Treatment.
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Page last updated 1 October 1997
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