Approved Drug Label (PDF)
4
Contraindications
Additions
and/or revisions underlined:
LEXIVA is contraindicated when
coadministered with drugs that are highly dependent on cytochrome P450 (CYP)3A4
for clearance and for which elevated plasma concentrations are associated with
serious and/or life-threatening events. These drugs and other
contraindicated drugs (which may lead to reduced efficacy of LEXIVA and
possible resistance) are listed below. The
list of contraindicated drugs applies to the use of LEXIVA with or
without ritonavir, unless otherwise indicated. If LEXIVA is coadministered with
ritonavir, reference should be made to the full prescribing information for
ritonavir for additional contraindications.
LEXIVA
is contraindicated when coadministered with the following drugs:
Table 2 converted
to a bulleted line listing; please refer to label for complete information.
Furthermore, the
drug Lomitapide
is added to the list of Lipid modifying
agents.
7
Drug Interactions
7.1
Cytochrome P450 Inhibitors and Inducers
Additions
and/or revisions underlined:
… Because ritonavir is a CYP2D6 inhibitor,
clinically significant interactions with drugs metabolized by CYP2D6 are
possible when coadministered with LEXIVA plus ritonavir. Ritonavir also
appears to induce CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6, as well as other
enzymes, including glucuronosyl transferase.
7.2
Established and Other Potentially Significant Drug Interactions
Newly
added information:
If LEXIVA is used in combination with
ritonavir, see full prescribing information for ritonavir for additional
information on drug interactions.
Table
6. Established and Other Potentially Significant Drug Interactions
Lipid
Modifying Agents: Addition of Lovastatin,
simvastatin and Other Lipid modifying
agents (Lomitapide) to table; please
refer to label for complete information.
8
Use in Specific Populations
8.1 Pregnancy
Extensively
changed; please refer to label for complete information.
Approved Drug Label (PDF)
5
Warnings and Precautions
5.7 Increase in Body Fat
(Subsection title has been revised; additions and/or revisions are underlined)
Increase of body
fat has been observed in patients receiving protease inhibitors, including LEXIVA…
7
Drug Interactions
7.3 Established and Other Potentially Significant Drug Interactions
Table 7.
Established and Other Potentially Significant Drug Interactions (Table has
been revised; please refer to label)
8
Use in Specific Populations
8.1 Pregnancy
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion;
additions and/or revisions are
underlined)
Pregnancy
Exposure Registry
There is a
pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LEXIVA during pregnancy.
Healthcare providers are encouraged to register patients by calling the
Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.
Risk Summary
There are
insufficient prospective pregnancy data from the Antiretroviral Pregnancy
Registry (APR) to adequately assess the risk of adverse developmental outcomes.
Fosamprenavir use during pregnancy has been evaluated in a limited number of
women as reported by the APR. Available data from the APR show 2 birth defects
in 109 first trimester exposures and 2 birth defects in 36 second and third
trimester exposures compared with the background rate for major birth defects
of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects
Program (MACDP). The estimated rate of miscarriage in clinically recognized
pregnancies in the U.S. general population is 15% to 20%. The background risk
for major birth defects and miscarriage for the indicated population is
unknown. Methodological limitations of the APR include the use of MACDP as the
external comparator group. The MACDP population evaluates women and infants
from a limited geographic area, and does not include birth defects in pregnancy
outcomes for births that occurred at less than 20 weeks’ gestation.
In animal
reproduction studies, no evidence of major adverse developmental outcomes was observed
following oral administration of fosamprenavir. Systemic exposure to amprenavir (the active
ingredient) was less than (rabbits) or up to 2 times (rats) those in
humans at the maximum recommended human dose (MRHD) with or without
ritonavir. In contrast, oral administration of amprenavir was
associated with abortions in pregnant rabbits at doses that produced approximately
one-twentieth the human exposure at the MRHD.
In the rat pre-
and post-natal development study, toxicities to the offspring, including
reduced survival and reproductive performance, were observed at maternal systemic exposures (AUC) to amprenavir
that were approximately 2 times the exposure in humans at the MRHD
of fosamprenavir alone or approximately the same as those seen in humans
following administration of the MRHD of fosamprenavir in combination with
ritonavir.
Data
Human Data: Based on prospective reports to the APR of approximately 146 live
births following exposure to fosamprenavir-containing regimens (including 109
live births exposed in the first trimester and 36 live births exposed in the
second and third trimesters) there were 4 birth defects reported in live-born
infants.
Animal Data: Fosamprenavir was administered orally to pregnant rats (300, 820, or
2,240 mg per kg per day) and rabbits (74.8, 224.3, or 672.8 mg per kg per day) on
gestation Days 6 to 17 and Days 7 to 20, respectively. No major adverse effects
on embryo-fetal development were observed at these dose levels, resulting in
exposures (AUC0-24 h) approximately 2 times (rats) and 0.8 times (rabbits)
human exposures at the MRHD of fosamprenavir alone or 0.7 times (rats) and 0.3 times
(rabbits) human exposures at the MRHD of fosamprenavir in combination with ritonavir.
However, increased incidence of abortion was observed in rabbits administered a
maternally toxic dose of fosamprenavir (672.8 mg per kg per day). In a study
where amprenavir was administered orally to pregnant rabbits (25, 50, or 100 mg
per kg per day) on gestation Days 8 to 20, increased abortions and an increased
incidence of minor skeletal variations (deficient ossification of the femur,
humerus, and trochlea) were observed at doses that produced approximately
one-twentieth the exposure seen at the MRHD.
In the rat pre-
and post-natal development study, fosamprenavir was administered orally (300, 820,
or 2,240 mg per kg per day) on gestation Day 6 to lactation/post-partum Day 20.
Fosamprenavir caused a reduction in pup survival and body weights. In surviving
female offspring from the high-dose group, an increased time to successful mating,
an increased length of gestation, a reduced number of uterine implantation
sites per litter, and reduced gestational body weights were observed. Systemic
exposure (AUC0-24 h) to amprenavir in rats was approximately 2 times the
exposures in humans at the MRHD of fosamprenavir alone or approximately the
same as those seen in humans at the MRHD of fosamprenavir in combination with
ritonavir.
8.2 Lactation
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion;
additions and/or revisions are
underlined)
Risk Summary
…
There is no
information available on the presence of amprenavir in human milk, the effects
of the drug on the breastfed infant, or the effects of the drug on milk
production. When administered to lactating rats, amprenavir was present in milk. Because of the potential for (1)
HIV-1 transmission (in HIV-negative infants), (2) developing viral
resistance (in HIV-positive infants), and (3) serious adverse reactions in a
breastfed infant, instruct mothers not to breastfeed if they are
receiving LEXIVA.
Data
Amprenavir was
excreted into the milk of lactating rats following a single dose of amprenavir (100
mg per kg); a maximal milk concentration was achieved 2 hours
post-administration at a milk concentration approximately 1.2 times that of
maternal plasma concentrations.
8.3 Females and Males of Reproductive Potential
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion;
additions and/or revisions are
underlined)
Contraception
Use of LEXIVA
may reduce the efficacy of combined hormonal contraceptives. Advise patients using
combined hormonal contraceptives to use an effective alternative contraceptive
method or an additional barrier method of contraception.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions and/or
revisions are underlined)
Contraception
Instruct patients
receiving combined hormonal contraception to use an effective
alternative contraceptive method or an additional barrier method during
therapy with LEXIVA because hormonal levels may decrease, and if used in
combination with LEXIVA and ritonavir, liver enzyme elevations may occur.
Severe Skin
Reactions
Advise patients
that skin reactions ranging from mild to severe, including Stevens-Johnson Syndrome,
have been reported with LEXIVA. Advise patients to discontinue LEXIVA immediately
for severe or life-threatening skin reactions or for moderate rashes
accompanied by systemic symptoms.
Hepatic Toxicity
Advise patients
that it is recommended to have laboratory testing before and during therapy as patients
with underlying hepatitis B or C or marked elevations of transaminases prior to
treatment may be at increased risk for developing or worsening transaminase
elevations with use of LEXIVA, particularly at higher than recommended doses
which should not be used.
Immune
Reconstitution Syndrome
Advise patients
to inform their healthcare immediately of any signs or symptoms of infection as
inflammation from previous infection may occur soon after combination
antiretroviral therapy, including LEXIVA is started.
Increase in Body
Fat
Inform patients
that an increase of body fat may occur in patients receiving protease
inhibitors, including LEXIVA, and that the cause and long-term health
effects of these conditions are not known at this time.
Lipid Elevations
Advise patients
that it is recommended to have laboratory testing before and during therapy as increases
in the concentration of triglycerides and cholesterol have been reported with
use of LEXIVA.
Pregnancy
Registry
Advise patients
that there is a pregnancy exposure registry that monitors pregnancy outcomes in
women exposed to LEXIVA during pregnancy.
Lactation
Instruct women with HIV-1 infection not to breastfeed
because HIV-1 can be passed to the baby in the breast milk.
Missed Dose
Instruct patients
that if they miss a dose of LEXIVA, to take it as soon as they remember.
Advise patients not to double their next dose or take more than the
prescribed dose.
PATIENT INFORMATION
(Additions and/or revisions are underlined)
What is the most
important information I should know about LEXIVA?
…
LEXIVA can
cause serious side effects, including:
For more information about side effects, see
“What are the possible side effects of LEXIVA?”
What is LEXIVA?
LEXIVA is a
prescription medicine that is used together with other antiretroviral
medicines to treat human immunodeficiency virus 1 (HIV-1) infection.
…
Do not take
LEXIVA if you:
If you are
taking LEXIVA with ritonavir, do not take the following medicines:
flecainide
propafenone
lurasidone
Before taking LEXIVA, tell your healthcare
provider about all of your medical conditions, including if you:
Pregnancy Registry. There is a pregnancy registry for women who
take LEXIVA during pregnancy…
…Some medicines
interact with LEXIVA.
Especially tell
your healthcare provider if you take:
You can ask your
healthcare provider or pharmacist for a list of medicines that interact with
LEXIVA. Do not start taking a new
medicine without telling your healthcare provider. Your healthcare provider
can tell you if it is safe to take LEXIVA with other medicines.
How should I take LEXIVA?
Take
LEXIVA exactly as your healthcare provider tells you to take it.
If you
miss a dose of LEXIVA, take it as soon as you remember. Do not take 2 doses
at the same time or take more than your healthcare provider tells you to take.
LEXIVA tablets may be taken with or without
food.
Do not run out of LEXIVA. The virus in your blood
may increase and the virus may become harder to treat. When your supply starts
to run low, get more from your healthcare provider or pharmacy.
What are the
possible side effects of LEXIVA?
LEXIVA may cause
serious side effects including:
See
“What is the most important information I should know about LEXIVA?”
Increase in body fat. An increase in
body fat can happen in people who take protease inhibitors, including LEXIVA…
Changes
in blood tests. Some people have changes in blood tests while taking LEXIVA. These
include an increase in liver function tests, blood fat levels (cholesterol
and triglycerides) and decrease in red blood cells…
The most common
side effects of LEXIVA in adults include:
The most
common side effects of LEXIVA in children include vomiting and
decrease in white blood cells.
How should I
store LEXIVA?
Approved Drug Label (PDF)
4
Contraindications
Table 2. Drugs
Contraindicated with LEXIVA (Information in the table applies to
LEXIVA with or without ritonavir, unless
otherwise indicated.)
Drug Class/Drug Name
Antipsychotics (added):
Lurasidone
Clinical
Comment: POTENTIAL for serious
and/or life-threatening reactions if LEIVA is co-administered with ritonavir.
Pimozide
Clinical Comment: POTENTIAL for
serious and/or life-threatening reactions such as cardiac arrhythmias.
7
Drug Interactions
7.3 Established and Other
Potentially Significant Drug Interactions
Table 7. Established and
Other Potentially Significant Drug Interactions (updated)
Antipsychotics:
Lurasidone
Effect on
Concentration of Amprenavir or Concomitant Drug- Concentration of Lurasidone
will increase.
Clinical
Comment:
LEXIVA:
If coadministration is necessary,
reduce the lurasidone dose. Refer to the lurasidone prescribing information for
concomitant use with moderate CYP3A4 inhibitors.
LEXIVA/ritonavir: Use of
lurasidone is contraindicated.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT
INFORMATION (updated)
Who should not
take LEXIVA?
Do not take
LEXIVA if you take any of the following medicines:
·
lurasidone (LATUDA®) (added)
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