|
 What
is Prezista?
PREZISTA
(darunavir), is a prescription medicine. It
is one treatment option in the class of HIV
(human immunodeficiency virus) medicines known
as protease inhibitors (PI).
PREZISTA is always used with 100 mg ritonavir
(Norvir ® ) in combination with other HIV
medicines for the treatment of HIV infection
in adults
•
The
use of other medicines active against HIV in
combination with PREZISTA/ritonavir (Norvir
® ) may increase the likelihood of your
overall treatment response. Your health care
professional will work with you to find the
right combination of other HIV medicines.
•
The
long-term effects of PREZISTA therapy are unknown
at this time. It is important that you remain
under the care of your health care professional.
How
does Prezista work?
•
PREZISTA™
blocks HIV protease, an enzyme which is needed
for HIV to multiply. When used with other anti-HIV
medicines, PREZISTA™ may reduce the amount
of HIV in your blood (called "viral load")
and increase your CD4 (T) cell count. HIV infection
destroys CD4 (T) cells, which are important
to the immune system. The immune system helps
fight infection. Reducing the amount of HIV
and increasing the CD4 (T) cell count may improve
your immune system and, thus, reduce the risk
of death or infections that can happen when
your immune system is weak (opportunistic infections).
•
PREZISTA™
is always taken with and at the same time as
100 mg of ritonavir
(Norvir), in combination with other anti-HIV
medicines.
Who
should not take Prezista?
•
Together
with your doctor, you need to decide whether
taking PREZISTA™ is right for you.
•
Do
not take PREZISTA™ if you:
•
are
allergic to darunavir or any of the other
ingredients in PREZISTA™
•
are
allergic to ritonavir (Norvir ® )
•
take any of the following types of medicines
because you could experience serious side
effects:
|
Type
of Drug
|
Examples
of Generic Names (Brand Names)
|
Antihistamines
(to treat allergy symptoms) |
astemizole
(Hismanal ® )
terfenadine (Seldane ® ) |
Ergot
Derivatives
(to treat migraine and headaches) |
dihydroergotamine
(D.H.E. 45 ® , Migranal ®
)
ergonovine
ergotamine (Wigraine ® , Ergostat
® , Cafergot ® ,
Ergomar ® )
methylergonovine |
Gastrointestinal
Motility Agent
(to treat some digestive conditions) |
cisapride
(Propulsid ® ) |
Neuroleptic
(to treat psychiatric conditions) |
pimozide
(Orap ® ) |
Sedative/hypnotics
(to treat trouble with sleeping and/or anxiety)
|
midazolam
(Versed ® )
triazolam (Halcion ® ) |
How
should I take Prezista?
•
Take
PREZISTA™ tablets every day exactly as
prescribed by your doctor. You must take ritonavir
(Norvir ® ) at the same time as PREZISTA™.
The usual dose is 600 mg (two 300 mg tablets)
of PREZISTA™, together with 100 mg (one
100 mg capsule) of ritonavir (Norvir ® ),
twice daily every day. It may be easier to remember
to take PREZISTA™ and ritonavir (Norvir
® ) if you take them at the same time every
day. If you have questions about when to take
PREZISTA™ and ritonavir (Norvir ® ),
your doctor can help you decide which schedule
works for you.
•
Take
PREZISTA™ and ritonavir (Norvir ® )
with food. The type of food is not important.
Swallow the tablets whole with a drink such
as water, milk, or any other nutritional drink.
Do not chew the tablets.
•
Continue
taking PREZISTA™ and ritonavir (Norvir
® ) unless your doctor tells you to stop.
Take the exact amount of PREZISTA™ and
ritonavir (Norvir ® ) that your doctor tells
you to take, right from the very start. To help
make sure you will benefit from PREZISTA™
and ritonavir (Norvir ® ), you must not
skip doses or interrupt therapy. If you don't
take PREZISTA™ and ritonavir (Norvir ®
) as prescribed, the beneficial effects of PREZISTA™
and ritonavir (Norvir ® ) may be reduced
or even lost.
•
If
you miss a dose of PREZISTA™ or ritonavir
(Norvir ® ) by more than 6 hours, wait and
then take the next dose of PREZISTA™ and
ritonavir (Norvir ® ) at the regularly scheduled
time. If you miss a dose of PREZISTA™ or
ritonavir (Norvir ® ) by less than 6 hours,
take your missed dose of PREZISTA™ and
ritonavir (Norvir ® ) immediately. Then
take your next dose of PREZISTA™ and ritonavir
(Norvir ® ) at the regularly scheduled time.
•
You
should always take PREZISTA™ and ritonavir
(Norvir ® ) together with food.
•
If
a dose of PREZISTA™ or ritonavir (Norvir
® ) is skipped, do not double the next dose.
Do not take more or less than your prescribed
dose of PREZISTA™ or ritonavir (Norvir
® ) at any one time.
What
are the possible side effects of Prezista?
•
Like
all prescription drugs, PREZISTA™ can cause
side effects. The following is not a complete
list of side effects reported with PREZISTA™
when taken either alone or with other anti-HIV
medicines. Do not rely on this leaflet alone
for information about side effects. Your doctor
can discuss with you a more complete list of
side effects.
•
Your
healthcare professional should do blood tests
prior to initiating combination treatment including
PREZISTA. Patients with liver diseases such
as hepatitis B and hepatitis C may have worsening
of their liver disease with PREZISTA™ and
may need more frequent monitoring of blood tests.
PREZISTA™ has been reported to cause liver
problems which may be life-threatening. It was
not always clear if PREZISTA™ caused these
liver problems because some patients had other
illnesses or were taking other medicines.
•
Mild
to moderate rash has been reported in 7% of
subjects receiving PREZISTA™. In some patients,
PREZISTA has been reported to cause a severe
or life-threatening rash. Contact your healthcare
provider if you develop a rash. Your healthcare
provider will advise you whether your symptoms
can be managed on therapy or whether PREZISTA™
should be stopped.
•
As
with other protease inhibitors, PREZISTA may
cause side effects, including:
•
high
blood sugar (hyperglycemia) and diabetes.
This can happen in patients taking PREZISTA™
or other protease inhibitor medicines. Some
patients have diabetes before starting treatment
with PREZISTA™ which gets worse. Some
patients get diabetes during treatment with
PREZISTA™. Some patients will need changes
in their diabetes medicine. Some patients
may need new diabetes medicine.
•
increased
bleeding in patients with hemophilia. This
may happen in patients taking PREZISTA™
as it has been reported with other protease
inhibitor medicines.
•
changes
in body fat. These changes can happen in patients
taking anti-HIV medicines. The changes may
include an increased amount of fat in the
upper back and neck, breast, and around the
back, chest, and stomach area. Loss of fat
from the legs, arms, and face may also happen.
The exact cause and long-term health effects
of these conditions are not known.
•
immune
reconstitution syndrome. In some patients
with advanced HIV infection (AIDS) and a history
of opportunistic infection, signs and symptoms
of inflammation from previous infections may
occur soon after anti-HIV treatment is started.
It is believed that these symptoms are due
to an improvement in the body's immune response,
enabling the body to fight infections that
may have been present with no obvious symptoms.
Important
Safety Information
•
PREZISTA,
together with NORVIR, has rarely been observed
to cause liver problems, which may be life-threatening.
It was not always clear if PREZISTA caused these
liver problems because some patients had other
illnesses or were taking other medicines. Your
health care professional should do blood tests
prior to initiating combination treatment including
PREZISTA. If you have chronic hepatitis B or
C infection, your health care professional should
check your blood tests more often because you
have an increased chance of developing liver
problems.
•
Talk
to your healthcare professional about the signs
and symptoms of liver problems. These may include
yellowing of your skin or whites of your eyes,
dark (tea colored) urine, pale colored stools
(bowel movements), nausea, vomiting, loss of
appetite, or pain, aching or sensitivity on
your right side below your ribs.
•
Skin
rashes have been reported in patients taking
PREZISTA. Rarely, PREZISTA has been reported
to cause a severe or life-threatening rash.
Contact your health care professional if you
develop a rash.
•
Taking
PREZISTA with certain medicines could cause
serious and/or life-threatening side effects
or may result in loss of its effectiveness.
Do not take PREZISTA if you are taking the following
medicines:
dihydroergotamine
(D.H.E.45 ® , Migranal ® ), ergonovine,
ergotamine (Wigraine ® , Ergostat ®
, Cafergot ® , Ergomar ® ), methylergonovine,
cisapride (Propulsid ® ), pimozide (Orap
® ), oral midazolam, triazolam (Halcion
® ), rifampin (Rifadin ® , Rifater
® , Rifamate ® ), indinavir (Crixivan
® ), lopinavir/ritonavir (Kaletra ®
), saquinavir (Invirase ® ), lovastatin
(Mevacor ® ), pravastatin (Pravachol ®
), simvastatin (Zocor ® ), or products
containing St. John's Wort.
•
Before
taking PREZISTA, tell your health care professional
if you are taking sildenafil (Viagra ® ),
vardenafil (Levitra ® ), tadalafil (Cialis
® ), atorvastatin (Lipitor ® ), atorvastatin/amlodipine
(Caduet ® ), or rosuvastatin (Crestor ®
). This is not a complete list of medicines.
Be sure to tell your health care professional
about all the medicines you are taking or plan
to take, including prescription and nonprescription
medicines, vitamins, and herbal supplements.
•
Tell
your health care professional if you are taking
estrogen-based contraceptives (birth control).
PREZISTA might reduce the effectiveness of estrogen-based
contraceptives. You must take additional precautions
for birth control such as condoms.
Before taking PREZISTA, tell your health care
professional if you have any medical conditions,
including allergy to sulfa medicines, diabetes,
liver problems (including hepatitis B or C)
or hemophilia.
Tell your health care professional if you are
pregnant or planning to become pregnant, or
are breastfeeding.
•
The
effects of PREZISTA on pregnant women or their
unborn babies are not known. You and your
health care professional will need to decide
if taking PREZISTA is right for you.
•
Do
not breastfeed if you are taking PREZISTA.
You should not breastfeed if you have HIV
because of the chance of passing HIV to your
baby.
•
High
blood sugar, diabetes or worsening of diabetes,
and increased bleeding in people with hemophilia
have been reported in patients taking protease
inhibitor medicines, including PREZISTA.
•
Changes
in body fat have been seen in some patients
taking HIV medicines, including PREZISTA. The
cause and long-term health effects of these
conditions are not known at this time.
•
As
with other protease inhibitors, taking PREZISTA
may strengthen the body's immune response enabling
it to begin to fight infections that have been
hidden. Patients may experience signs and symptoms
of inflammation that can include swelling, tenderness
or redness.
•
The
most common side effects related to taking PREZISTA
include diarrhea, nausea, headache, and abdominal
pain. Uncommon but severe side effects such
as inflammation of the pancreas and increased
blood fat levels have also been rarely reported.
This is not a complete list of all possible
side effects. If you experience these or other
symptoms, talk to your health care professional.
Do not stop taking PREZISTA or any other medicines
without first talking to your health care professional.
•
Please
refer to the ritonavir (Norvir ® ) Product
Information (PI and PPI) for additional information
on precautionary measures.
PREZISTA
should always be taken at the same time with
100 mg Norvir ® , in combination with other
HIV medicines as prescribed by your health care
professional. PREZISTA should also be taken
with food (the type of food is not important).
Clinical
Trials
Evidence
of the efficacy of darunavir and ritonavir in
antiretroviral treatment-experienced HIV positive
adults is shown in analyses of 24- and 48-week
data in two randomized, Phase IIb trials, POWER
1 (TMC114-C213) and
POWER 2 (TMC114-C202).
Both
of these trials consisted of 2 parts: an initial
partially-blinded, dose-finding part and a second
long-term part in which all patients were randomized
to either darunavir and ritonavir or an investigator-selected
antiretroviral regimen, then received the recommended
dose of darunavir 600 mg and ritonavir 100 mg.
Participants
were required to have a baseline HIV RNA (viral
load) of greater than 1000 copies/ml, had previous
treatment with PIs, non-nucleoside reverse transcriptase
inhibitors (NNRTIs), and nucleoside reverse
transcriptase inhibitors (NRTIs), and have at
least one primary PI mutation at screening,
and to be currently taking a stable PI-containing
regimen at screening for at least 8 weeks prior
to study entry.
•
24-week
Primary Analysis Findings
Analyses included 318 patients in TMC114-C213
and 319 patients in TMC114-C202. At 24 weeks,
the virologic response rate was evaluated in
patients receiving darunavir and ritonavir plus
an optimized background regimen (OBR) versus
a control group receiving an investigator-selected
PI-containing regimen plus an OBR.
The primary analysis from POWER 1 and 2 showed
that at 24 weeks, patients in the darunavir/r
arm were significantly more likely to achieve
a virologic response, achieve undetectable viral
load (less than 50 copies/mL) and have an increase
in CD4+ cell counts from baseline compared to
the patients in the control arm. An intent-to-treat
analysis demonstrated the following:
69.5 percent vs. 21 percent achieved a virologic
response defined as equal to or greater than
1.0 log10 reduction (90 percent reduction) in
viral load from baseline;
45 percent vs. 12.1 percent achieved undetectable
viral load (less than 50 copies/mL); and
Patients experienced a CD4+ cell mean increase
of 92 cells/mm3 vs.17 cells/mm3 from baseline.
•
Analysis
of Patients Reaching 48 Weeks of Treatment
Among 110 patients who had reached 48 weeks
of treatment in the darunavir/r arm (total n=131)
vs. 120 patients who had reached 48 weeks of
treatment in the control arm (total n=124),
intent-to-treat data showed the following:
61 percent vs. 15 percent had a virologic
response defined as equal to or greater than
1.0 log10 reduction (90 percent reduction)
in viral load from baseline
46 percent vs. 10 percent reached undetectable
viral load (less than 50 copies/mL)
Patients experienced a CD4+ cell mean increase
of 102 cells/mm3 vs.19 cells/mm3 from baseline
Among
patients reaching 48 weeks, the most commonly
reported adverse events among patients in the
darunavir/r arm vs. control arm were diarrhea
(20 percent vs. 28 percent), nausea (18 percent
vs. 13 percent), headache (15 percent vs. 20
percent), nasopharyngitis (14 percent vs. 11
percent) and fatigue (12 percent vs. 17 percent).
Discontinuations because of adverse events were
seven percent in the darunavir/r arm vs. five
percent in the control arm.
|
Pooled
POWER 1 and 2 Virologic Response Rates
|
|
|
Week
24
|
Week
48
|
|
Efficacy
parameter
|
TMC114/r
600/100mg bid (n=131)
|
CPI
(n=124)
|
P-value
|
TMC114/r
600/100mg bid (n=110)
|
CPI
(n=120)
|
P-value
|
|
Patients
with HIV RNA >=1.0 log10 reduction (%)
|
70
|
21
|
<0.001
|
61
|
15
|
<0.001
|
|
Patients
with HIV RNA <50 copies/mL (%)
|
45
|
12
|
<0.001
|
46
|
10
|
<=0.003
|
|
Mean
HIV RNA log10 reduction (copies/mL)
|
-
1.89
|
-
0.48
|
<0.001
|
-
1.63
|
-
0.35
|
<0.001
|
|
Mean
CD4 increase (cells/mm3)
|
92
|
17
|
<0.001
|
102
|
19
|
<=0.005
|
*
Lazzarin et al. TMC114 provides durable viral
load suppression in treatment-experienced patients:
POWER 1 and 2 combined week 48 analysis. 16th
International AIDS Conference. August 13-18, 2006.
Toronto, Canada. Abstract TUAB0104 (oral).
Resistance
and Cross Resistance
•
In
analyses of 3 different Phase IIb studies using
darunavir, multiple PI-resistant HIV-1 isolates
were collected from highly treatment-experienced
patients who received darunavir 600 mg and ritonavir
100 mg twice daily and experienced virologic
failure either by rebound or by never being
fully suppressed. These patients developed amino
acid substitutions that were associated with
decreased susceptibility to darunavir.
•
Cross
resistance to other PIs has been observed. Darunavir
has a less than tenfold decreased susceptibility
in cell culture against 90% of 3309 clinical
isolates resistant to amprenavir (Agenerase),
atazanavir (Reyataz), indinavir (Crixivan),
lopinavir (Kaletra), nelfinavir (Viracept),
ritonavir (Norvir), saquinavir (Invirase), and/or
tipranavir (Aptivus) showing that viruses to
these PIs remain susceptible to darunavir.
•
Darunavir-resistant
viruses were not susceptible to amprenavir,
atazanavir, indinavir, lopinavir, nelfinavir,
ritonavir, or saquinavir in cell culture. However,
six of nine darunavir-resistant viruses selected
in cell culture from PI-resistant viruses showed
a fold change in EC50 values less than 3 for
tipranavir, indicative of limited cross resistance
between darunavir and tipranavir. Of the viruses
isolated from patients experiencing virologic
failure taking darunavir 600 mg and ritonavir
100 mg twice daily, greater than 50% were still
susceptible to tipranavir, while less than 5%
were susceptible to the other PIs.
•
Cross
resistance between darunavir and NNRTIs, NRTIs,
and fusion inhibitors is unlikely because the
viral targets are different.
Pregnancy
•
Darunavir
is in FDA Pregnancy Category B. There are no
adequate and well-controlled studies conducted
in pregnant women. Reproduction studies conducted
with darunavir have shown no embryotoxicity
or teratogenicity in mice, rats, and rabbits.
•
To
monitor maternal-fetal outcomes of pregnant
women exposed to zidovudine (or other antiretrovirals),
an Antiretroviral Pregnancy Registry has been
established. Physicians may register patients
at http://www.APRegistry.com
or by calling 1-800-258-4263. It is not known
whether darunavir is excreted in human milk;
it is excreted in the milk of lactating rats.
Because of the potential for HIV transmission
and for serious adverse effects from darunavir
to the breastfed infant, women should be
instructed not to breastfeed while taking darunavir.
Drug
and Food Interactions
Darunavir
must always be taken with ritonavir 100 mg in
combination with other antiretroviral drugs.
Coadministration
of darunavir and ritonavir with efavirenz (Sustiva)
caused a decrease in darunavir AUC by 13% and
minimum serum concentrations (Cmin) by 31%,
while the AUC and Cmin of efavirenz increased
by 21% and 17%, respectively. The clinical significance
has not been established; however, this combination
of drugs should be used with caution.
Because
didanosine (Videx) must be administered on an
empty stomach, didanosine should be administered
one hour prior to or two hours after darunavir
and ritonavir dosing with food.
Coadministration
of darunavir and ritonavir with indinavir (Crixivan)
resulted in a serum concentration increase in
both darunavir and indinavir. The appropriate
dose of indinavir in combination with darunavir
and ritonavir has not been established.
Coadministration
of darunavir with lopinavir/ritonavir (Kaletra)
resulted in a 53% decrease in darunavir AUC.
Coadministration of darunavir and ritonavir
with saquinavir (Invirase) resulted in a 26%
decrease in darunavir AUC. Coadministration
of these drugs with darunavir is not recommended.
Both
darunavir and ritonavir are inhibitors of CYP3A.
Coadministration of darunavir and ritonavir
with drugs primarily metabolized by CYP3A may
result in increased plasma concentrations of
such drugs, which could increase or prolong
their therapeutic effect and adverse effects.
Carbamazepine,
phenobarbital, phenytoin, and rifampin are inducers
of CYP450 enzymes and should not be used in
combination with darunavir and ritonavir. St.
John's wort should also not be used concomitantly
with darunavir and ritonavir. Coadministration
of these drugs may cause significant decreases
in darunavir plasma concentrations and a loss
of therapeutic effect to darunavir.
Use
of some HMG-CoA reductase inhibitors, including
lovastatin and simvastatin, may require dose
adjustment if taken concurrently with darunavir
and ritonavir because of the potential of serious
reactions such as myopathy, including rhabdomyolysis.
Coadministration of darunavir and ritonavir
with other HMG-CoA reductase inhibitors, such
as atorvastatin and pravastatin, should be given
at the lowest possible dose of the statin with
careful patient monitoring.
Caution
must be used when antiarrhythmics, including
bepridil, lidocaine, quinidine, and amiodarone,
are used concurrently with darunavir and ritonavir.
Concentrations of antiarrhythmic drugs may increase.
Therapeutic concentration monitoring should
be used, if available, to guide patient treatment.
Concurrent
use of darunavir and ritonavir with warfarin
may decrease warfarin plasma concentrations,
and patients should be monitored carefully if
they are taking such a regimen.
Concomitant use of trazodone and darunavir and
ritonavir may increase plasma concentrations
of trazodone, leading to nausea, dizziness,
hypotension, and syncope. A lower dose of trazodone
should be considered in patients who require
this combination of drugs.
Concurrent
use of darunavir and ritonavir with clarithromycin
may require dose adjustment of the clarithromycin
dose in patients with impaired renal function.
Ketoconazole
and itraconazole are potent inhibitors as well
as substrates of CYP3A. Plasma concentrations
of these two drugs may increase in the presence
of darunavir and ritonavir. When coadministration
is required, the daily dose of azole should
not exceed 200 mg. Concurrent use of darunavir
and ritonavir with voriconazole has not been
studied. However, concomitant use of voriconazole
and 100 mg ritonavir twice daily decreased voriconazole
AUC by 39%. Therefore, patients receiving darunavir
and ritonavir should not receive voriconazole
unless the potential benefit outweighs the risk
to the patient.
Rifabutin
is an inducer and substrate of CYP450 enzymes.
Concomitant use of rifabutin with darunavir
and ritonavir is expected to increase rifabutin
plasma concentrations. It is recommended to
administer rifabutin at a dosage of 150 mg rifabutin
once every other day when coadministered with
darunavir and ritonavir.
Plasma
concentrations of calcium channel blockers,
including felodipine, nifedipine, and nicardipine,
may increase when given concurrently with darunavir
and ritonavir. Caution is warranted and clinical
monitoring of patients is recommended.
Plasma
concentrations of immunosuppressants, including
cyclosporine, tacrolimus, and sirolimus, may
be increased when coadministered with darunavir
and ritonavir. Therapeutic concentration monitoring
for the immunosuppressive agent is recommended
when these drugs are taken concurrently.
When
methadone is coadministered with darunavir and
ritonavir, patients should be monitored for
abstinence syndrome, as ritonavir is known to
induce the metabolism of methadone, leading
to a decrease in methadone's concentrations.
An increase in methadone dosage may be considered
based on the clinical response.
Plasma
concentrations of ethinyl estradiol may be decreased
when it is used with darunavir and ritonavir
due to the induction of its metabolism by ritonavir.
Alternative or additional contraceptive measures
should be used when estrogen-based contraceptives
are coadministered with darunavir and ritonavir.
Concomitant
administration of darunavir and ritonavir with
PDE-5 inhibitors, including sildenafil, vardenafil,
and tadalafil, should be done with caution.
PDE-5 inhibitor dosing should not exceed the
doses as indicated by the manufacturer.
Darunavir
and ritonavir with selective serotonin reuptake
inhibitors (SSRIs) sertraline and paroxetine
should be taken concomitantly with caution.
The recommended approach is a careful dose titration
of the SSRI based on a clinical assessment of
antidepressant response. In addition, patients
on a stable dose of sertraline and paroxetine
who start treatment with darunavir and ritonavir
should be monitored for antidepressant response.
Contraindications
Darunavir
must always be taken with ritonavir 100 mg in
combination with other antiretroviral drugs.
Both
darunavir and ritonavir are both inhibitors
of CYP3A. Coadministration of darunavir and
ritonavir with drugs primarily metabolized by
CYP3A may result in increased plasma concentrations
of such drugs, which could increase or prolong
their therapeutic effect and adverse effects
(See section on Drug Interactions above)
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