Approved Drug Label (PDF)
4
Contraindications
Newly added information:
Darunavir and
cobicistat are both inhibitors of the cytochrome P450 3A (CYP3A) isoform. PREZCOBIX
should not be co-administered with medicinal products
that are highly
dependent on CYP3A for
clearance and for which increased plasma concentrations are associated with
serious and/or life threatening events (narrow therapeutic index). Darunavir
and cobicistat are both substrates of the cytochrome P450 3A (CYP3A)
isoform. Co- administration of PREZCOBIX with CYP3A inducers may lead to lower
exposures of darunavir and cobicistat and potential loss of efficacy of
darunavir and possible resistance. Examples of drugs that are contraindicated
for co- administration with PREZCOBIX [see Drug Interactions (7.3)
and Clinical Pharmacology (12.3)] are listed below.
7
Drug Interactions
7.3 Established and Other Potentially Significant Drug Interactions
Additions and/or
revisions underlined:
The
table includes examples of potentially significant interactions but is
not all inclusive, and
therefore the label of each drug that is co-administered with PREZCOBIX should
be consulted for information related to the route of metabolism, interaction pathways,
potential risks, and specific actions to be taken with regard to
co-administration. For the list of examples of contraindicated
drugs, [see Contraindications (4)].
8
Use in Specific Populations
8.1 Pregnancy
Additions and/or
revisions underlined:
Risk
Summary
PREZCOBIX
is not recommended during pregnancy because of substantially lower exposures
of darunavir and cobicistat during the second and third trimesters [see Dosage and Administration (2.5)]. A
study evaluating the pharmacokinetics of antiretrovirals during pregnancy
demonstrated substantially lower exposures of darunavir and cobicistat in the
second and third trimesters compared to the post-partum period (see Data) and [see Clinical Pharmacology (12.3)].
Prospective
pregnancy data from the APR are not sufficient to adequately assess the risk of
birth defects or miscarriage. However, available data from the APR show
no statistically significant difference in the overall risk of
major birth defects for darunavir and cobicistat 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) (see Data).
Data
Human Data
Additions and/or
revisions underlined:
Prospective
reports from the APR of overall major birth defects in pregnancies exposed to
the components of PREZCOBIX are compared with a U.S. background major birth
defect rate. Methodological limitations of the APR include the use of MACDP as
the external comparator group. Limitations of using an external comparator
include differences in methodology and populations, as well as confounding due
to the underlying disease.
Darunavir: Based on
prospective reports to the APR of over 980 exposures to darunavir-
containing regimens during pregnancy resulting in live births (including
over 660 exposed in the first trimester and over 320 exposed in
the second/third trimester), the prevalence of birth defects in live births was
3.6% (95% CI: 2.3% to 5.3%) with first trimester exposure
to darunavir- containing regimens and 2.5% (95% CI: 1.1% to 4.8%)
with second/third trimester exposure to darunavir-containing regimens.
Cobicistat: Based on
prospective reports to the APR of over 570 exposures to cobicistat- containing
regimens during pregnancy resulting in live births (including over 480 exposed
in the first trimester and over 80 exposed in the second/third trimester), the
prevalence of birth defects in live births was 3.7% (95% CI: 2.2% to 5.7%) and
1.1% (95% CI: 0.0% to 6.2%) with first and second/third trimester,
respectively, to cobicistat-containing regimens.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATION
Additions and/or revisions underlined:
Do not take
PREZCOBIX with any medication that contains:..
Serious problems can happen if you take any of these
medicines with PREZCOBIX. This is not a complete list of medicines.
Therefore, tell your healthcare provider about all medicines you take.
Tell your
healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, topical creams,
vitamins, and herbal supplements. Some medicines interact with PREZCOBIX. Keep a list of your medicines to show your healthcare
provider and pharmacist.
Approved Drug Label (PDF)
5
Warnings and Precautions
5.5 Risk of Serious Adverse Reactions or Loss of Virologic Response Due to Drug Interactions
(Additions and/or revisions underlined)
Initiation
of PREZCOBIX, which inhibits CYP3A, in patients
receiving medications
metabolize
d by CYP3A, or initiation of medications metabolized by CYP3A in patients already receiving
PREZCOBIX may increase
plasma concentrations of medications metabolized by CYP3A and reduce
plasma concentrations of active metabolite(s) formed by CYP3A. Initiation of medications that inhibit or induce CYP3A may respectively increase or decrease concentrations of PREZCOBIX.
These interactions may lead to:
clinically
significant adverse reactions, potentially leading
to severe, life threatening, or fatal events from higher exposures of concomitant medications.
clinically significant adverse reactions from higher exposures of PREZCOBIX.
loss of therapeutic effect of the concomitant medications
from lower exposures
of active metabolite(s).
7
Drug Interactions
7.1 Potential for PREZCOBIX to Affect Other Drugs
(Newly added information)
Co-administration of PREZCOBIX with drugs that have active metabolite(s) formed by CYP3A may result in reduced
plasma concentrations of these active metabolite(s), potentially
leading to loss of their therapeutic effect. . .
7.3 Established and Other Potentially Significant Drug Interactions
(Table 1 updated with the addition of information
about platelet aggregation inhibitors clopidogrel and prasugrel)
Approved Drug Label (PDF)
6
Adverse Reactions
6.1 Clinical Trials Experience
Additions and/or revisions underlined:
Clinical Trials in Adults
During the darunavir clinical development program, where
darunavir was co-administered with ritonavir 100 mg once or twice daily, the
most common clinical adverse reactions …
Newly added information:
Clinical Trials in Pediatric Patients
No clinical trials with PREZCOBIX were performed in
pediatric patients. However, the safety of the components of PREZCOBIX,
darunavir and cobicistat, co-administered with two nucleoside reverse
transcriptase inhibitors was evaluated in pediatric subjects of 12 to less than
18 years of age with HIV-1 infection through clinical trial GS-US-216-0128
(virologically-suppressed, N=7 with weight greater than or equal to40 kg)
through Week 48. Safety analyses of this trial in these pediatric subjects did
not identify new safety concerns compared to the known safety profile of
PREZCOBIX in adult subjects [see Clinical
Studies (14.2)].
8
Use in Specific Populations
8.4 Pediatric Use
Additions and/or revisions underlined:
The safety and effectiveness of PREZCOBIX for the
treatment of HIV-1 infection in pediatric patients weighing at least 40
kg was established through a trial with components of PREZCOBIX. Use of
PREZCOBIX in this group is supported by evidence from adequate and
well-controlled studies in adults with additional pharmacokinetic, safety, and
virologic data from a study of components of PREZCOBIX (Trial GS-US-216-0128)
in pediatric subjects with HIV-1 infection aged 12 to less than 18 years [see Adverse Reactions (6.1), Clinical Pharmacology
(12.3), and Clinical Studies (14.2)].
The safety and effectiveness of PREZCOBIX have not
been established in pediatric patients weighing less than 40 kg.
Darunavir, a component of PREZCOBIX is not recommended in pediatric patients
below 3 years of age because of toxicity and mortality observed in juvenile
rats dosed with darunavir.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATION
What is PREZCOBIX?
Additions and/or revisions underlined:
PREZCOBIX is a prescription medicine that is used with other
HIV-1 medicines to treat HIV-1 infection in adults and in children who weigh
at least 88 pounds (40 kg).
HIV-1 is the virus that causes Acquired Immune Deficiency
Syndrome (AIDS).
PREZCOBIX contains the prescription medicines darunavir and
cobicistat.
It is not known if PREZCOBIX is safe and effective in
children weighing less than 88 pounds (40 kg).
Before taking PREZCOBIX, tell your healthcare provider
about all your medical conditions, including if you:
Approved Drug Label (PDF)
4
Contraindications
(additions
underlined)
PREZCOBIX
is contraindicated in patients receiving the following co-administered drugs.
…
…
…
5
Warnings and Precautions
5.10 Immune Reconstitution Syndrome
(additions
underlined)
…
Autoimmune
disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome and
autoimmune hepatitis) have also been reported to occur in the setting of
immune reconstitution; however, the time to onset is more variable, and can
occur many months after initiation of antiretroviral treatment.
6
Adverse Reactions
7
Drug Interactions
7.3 Established and Other Potentially Significant Drug Interactions
(extensive
additions and deletions, please refer to label)
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATION
(additions
underlined)
…
Who should not take
PREZCOBIX?
Do not take
PREZCOBIX with
any medicine that contains:
…
…
…
Approved Drug Label (PDF)
4
Contraindications
4 CONTRAINDICATIONS
(Additions and/or revisions are
underlined)
…
Hepatitis
C direct acting antiviral: elbasvir/grazoprevir
HMG-CoA
reductase ![]()
Lipid modifying agents: lomitapide,
lovastatin, simvastatin
PDE-5
inhibitor: sildenafil when used for
treatment of pulmonary arterial
hypertension
Sedatives/hypnotics:
orally administered midazolam, triazolam
8
Use in Specific Populations
8.1 Pregnancy
Additions and/or revisions are
underlined)
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors
pregnancy outcomes in individuals exposed to PREZCOBIX during
pregnancy. Healthcare providers are encouraged to register
patients by calling the Antiretroviral Pregnancy Registry
(APR) 1-800-258-4263![]()
![]()
.
Risk
Summary
There are insufficient data with PREZCOBIX
in pregnant individuals from the APR to inform a drug-associated risk of pregnancy outcomes. Available
data from the APR show no difference in rate of overall birth defects for darunavir 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) (see Data). The APR uses the MACDP as the U.S. reference
population for birth defects in the general population. The MACDP evaluates
pregnant individuals and infants from a limited
geographic area and does not include outcomes for births that occurred at less than
20 weeks gestation.
…
Clinical
Considerations
Not Recommended During Pregnancy
PREZCOBIX
is not recommended for use during pregnancy because of substantially lower
exposures of darunavir and cobicistat during pregnancy.
PREZCOBIX
should not be initiated in pregnant individuals. An alternative regimen
is recommended for individuals who become pregnant during therapy with
PREZCOBIX.
Data
Human Data
Darunavir/Cobicistat:
PREZCOBIX in combination with a background regimen was evaluated in a
clinical trial of 7 pregnant individuals taking PREZCOBIX prior to
enrollment and who were willing to remain on PREZCOBIX throughout the study.
The study period included the second and third trimesters, and through 12 weeks
postpartum. Six pregnant individuals completed the trial.
Exposure
to darunavir and cobicistat as part of an antiretroviral regimen was
substantially lower during the second and third trimesters of pregnancy compared
with postpartum.
One out of 6 pregnant
individuals who completed the study experienced virologic failure with
HIV-1 RNA >1,000 copies/mL from the third trimester visit through the
postpartum period. Five pregnant individuals had sustained virologic
response (HIV RNA <50 copies/mL) throughout the study period. There are no
clinical data on the virologic response when PREZCOBIX is initiated during
pregnancy.
…
8.3 Females and Males of Reproductive Potential
(Newly
added subsection)
Contraception
Additional or alternative (non-hormonal) forms of
contraception should be considered when estrogen-containing contraceptives are
co-administered with PREZCOBIX. For
co-administration with drospirenone, clinical monitoring is recommended due to the potential
for hyperkalemia. No data are available
to make recommendations on co-administration with other hormonal
contraceptives.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions
and/or revisions are underlined)
…
Pregnancy
Advise patients that PREZCOBIX is not recommended
during pregnancy and to alert their healthcare provider if they get
pregnant while taking PREZCOBIX [see
Use in Specific Populations (8.1)]. Inform patients that there is an
antiretroviral pregnancy registry to monitor fetal outcomes of pregnant individuals
exposed to PREZCOBIX [see Use
in Specific Populations (8.1)].
Lactation
Instruct individuals with HIV-1 infection not to breastfeed
because HIV-1 can be passed to the baby in breast milk.
…
PATIENT INFORMATION
(Additions and/or revisions are
underlined)
...
Who should not take PREZCOBIX?
Do not take PREZCOBIX with
any medicine that contains:
Before taking PREZCOBIX, tell your healthcare
provider about all your medical conditions, including if you:
have liver problems, including
hepatitis B or hepatitis C
have kidney problems
are allergic to sulfa
(sulfonamide)
have diabetes
have hemophilia
have any other medical condition
are pregnant or plan to become
pregnant.
Approved Drug Label (PDF)
4
Contraindications
Additions and/or revisions underlined:
PREZCOBIX is contraindicated
in patients receiving the following co-administered drugs:
Table 1: Drugs That Are Contraindicated with Prezcobix reformatted to a bulleted line
listing; please refer to label for complete information.
6
Adverse Reactions
6.2 Postmarketing Experience
Newly added information:
The following events
have been identified during post-approval use of darunavir. Because these events
are reported voluntarily from a population of uncertain size, it is not always possible
to reliably estimate their frequency or establish a causal relationship to drug
exposure.
Metabolism and Nutrition
Disorders:
Redistribution of body
fat
Musculoskeletal and
Connective Tissue Disorders:
Rhabdomyolysis (associated
with co-administration with HMG-CoA reductase inhibitors)
Skin and Subcutaneous
Tissue Disorders
Toxic epidermal necrolysis,
acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic
symptoms
7
Drug Interactions
7.3 Established and Other Potentially Significant Drug Interactions
Table 2 is now Table
1: Established and Other Potentially Significant* Drug Interactions: Alterations
in Dose or Regimen May Be Recommended
Addition of the phrase (this table is not all
inclusive) in the text leading up to the table.
8
Use in Specific Populations
8.1 Pregnancy
Additions and/or revisions underlined:
Clinical Considerations
Not Recommended During Pregnancy
PREZCOBIX is not
recommended for use in pregnant women because of substantially lower exposures
of darunavir and cobicistat during pregnancy.
PREZCOBIX should not
be initiated in pregnant women. An alternative regimen is recommended for women
who become pregnant during therapy with PREZCOBIX.
Data
Human Data
Darunavir/Cobicistat: PREZCOBIX in combination
with a background regimen was evaluated in a clinical trial of 7 pregnant women
taking PREZCOBIX prior to enrollment and who were willing to remain on PREZCOBIX
throughout the study. The study period included the second and third trimesters,
and through 12 weeks postpartum. Six women completed the trial.
Exposure to darunavir
and cobicistat as part of an antiretroviral regimen was substantially lower during
the second and third trimesters of pregnancy compared with postpartum.
One out of 6 women
who completed the study experienced virologic failure with HIV-1 RNA
Greater than 1,000
copies/mL from the third trimester visit through the postpartum period. Five women
had sustained virologic response (HIV RNA less than 50 copies/mL) throughout the
study period. There are no clinical data on the virologic response when PREZCOBIX
is initiated during pregnancy.
There were no new clinically
relevant safety findings compared with the known safety profile of PREZCOBIX in
HIV-1-infected adults.
Darunavir: Based on prospective reports to the APR of
679 live births following exposure to darunavir-containing regimens during pregnancy
(including 425 exposed in the first trimester and 254 exposed in the
second/third trimester) …
The prevalence of birth
defects in live births was 2.1% (95% CI: 1.0% to 4.0%) with
first trimester exposure to darunavir-containing regimens and 2.4%
(95% CI: 0.9% to 5.1%) with second/third trimester exposure to darunavir-containing
regimens.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions and/or revisions underlined:
Pregnancy
Advise patients that
PREZCOBIX is not recommended in pregnant women and to alert their healthcare provider
if they get pregnant while taking PREZCOBIX. Inform patients that there is an antiretroviral
pregnancy registry …
Approved Drug Label (PDF)
7
Drug Interactions
7.3 Established and Other Potentially Significant Drug Interactions
(Subsection title has been revised; additions and/or revisions are underlined)
…These recommendations are based on either drug interaction
trials or predicted interactions due to the expected magnitude of interaction
and potential for serious adverse events or loss of therapeutic effect.
Table 2: Established
and Other Potentially Significant* Drug Interactions: Alterations in Dose
or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted
Interaction
(Table has been revised; please refer to
label)
7.4 Drugs without Clinically Significant Interactions with PREZCOBIX
(Additions and/or revisions are underlined)
Clinically relevant drug-drug interactions have not been
observed or are not anticipated with concomitant use of darunavir and
cobicistat with rilpivirine, dolutegravir, raltegravir, abacavir,
emtricitabine, emtricitabine/tenofovir alafenamide, tenofovir DF, lamivudine,
stavudine, zidovudine, or acid modifying medications (antacids, H2-receptor
antagonists, proton pump inhibitors).
Approved Drug Label (PDF)
7
Drug Interactions
7.3 Established and Other Potentially Significant Drug Interactions
(Subsection title has been revised; additions and/or revisions are underlined)
…These recommendations are based on either drug interaction
trials or predicted interactions due to the expected magnitude of interaction
and potential for serious adverse events or loss of therapeutic effect.
Table 2: Established
and Other Potentially Significant* Drug Interactions: Alterations in Dose
or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted
Interaction
(Table has been revised; please refer to
label)
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATION
(Additions and/or revisions are underlined)
Who should not take
PREZCOBIX?
Do not take PREZCOBIX
with any of the following medicines:
Approved Drug Label (PDF)
7
Drug Interactions
7.1 Potential for PREZCOBIX to Affect Other Drugs
(Additions and/or revisions are underlined)
Darunavir co-administered with cobicistat is an
inhibitor of CYP3A and CYP2D6. Cobicistat inhibits the following
transporters: P-glycoprotein (P-gp), BCRP, MATE1, OATP1B1 and OATP1B3.
Therefore, co-administration of PREZCOBIX with drugs that are primarily
metabolized by CYP3A and/or CYP2D6 or are substrates of P-gp, BCRP, MATE1,
OATP1B1 or OATP1B3 may result in increased plasma concentrations of such drugs,
which could increase or prolong their therapeutic effect and can be associated
with adverse events (see Table 2).
7.2 Potential for Other Drugs to Affect PREZCOBIX
(Additions and/or revisions are underlined)
…Co-administration of PREZCOBIX and drugs that induce
CYP3A activity are expected to increase the clearance of darunavir and
cobicistat, resulting in lowered plasma concentrations of darunavir and
cobicistat which may lead to loss of therapeutic effect and development of
resistance…
7.3 Potentially Significant Drug Interactions
Table 2: Potentially
Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended
Based on Drug Interaction Trials or Predicted Interaction (see
Contraindications (4) for a complete list of contraindicated drugs) (Table
has been revised; please refer to label)
7.4 Drugs without Clinically Significant Interactions with PREZCOBIX
(Newly added subsection title)
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 PREZCOBIX during pregnancy.
Healthcare providers are encouraged to register patients by calling the
Antiretroviral Pregnancy Registry (APR) 1-800-258-4263.
Risk Summary
There are insufficient data with PREZCOBIX in pregnant
women from the APR to inform a drug-associated risk of pregnancy outcomes.
Available data from the APR show no difference in rate of overall birth defects
for darunavir 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 APR uses the MACDP as the U.S. reference population for
birth defects in the general population. The MACDP evaluates women and infants
from a limited geographic area and does not include outcomes for births that
occurred at less than 20 weeks gestation.
The rate of miscarriage is not reported in the APR. The
estimated background rate of miscarriage in clinically recognized pregnancies
in the U.S. general population is 15-20%. The background risk of major birth
defects and miscarriage for the indicated population is unknown.
In animal reproduction studies, no adverse developmental
effects were observed when the components of PREZCOBIX were administered
separately at darunavir exposures less than 1 (mice and rabbits) and 3-times
(rats), and at cobicistat exposures 1.6 (rats) and 3.8 (rabbits) times human
exposures at the recommended daily dose of these components in PREZCOBIX. No
adverse developmental effects were seen when cobicistat was administered to
rats through
lactation at cobicistat exposures up to 1.2 times the human exposure at the
recommended therapeutic dose.
Clinical Considerations
Dose Adjustment
During Pregnancy and the Postpartum Period
Dosing recommendations cannot be made because the
pharmacokinetics, safety, and efficacy of PREZCOBIX cannot be predicted from
studies of other darunavir-containing regimens in pregnant women.
Data
Human Data
Darunavir:
Based on prospective reports to the APR of 615 live births following exposure
to darunavir-containing regimens during pregnancy (including 385 exposed in the
first trimester and 230 exposed in the second/third trimester), there was no
difference in rate of overall birth defects for darunavir compared with the
background rate for major birth defects in a U.S. reference population of the
MACDP.
The prevalence of birth defects in live births was 2.6%
(95% CI: 1.2% to 4.7%) with first trimester exposure to darunavir-containing
regimens and 1.7% (95% CI: 0.5% to 4.4%) with second/third trimester exposure
to darunavir-containing regimens.
Cobicistat:
Insufficient numbers of pregnancies with exposure to cobicistat have been
reported to the APR to estimate the rate of birth defects.
Animal Data
Darunavir: Reproduction
studies conducted with darunavir showed no embryotoxicity or teratogenicity in
mice (doses up to 1000 mg/kg from gestation day (GD) 6-15 with darunavir
alone) and rats (doses up to 1000 mg/kg from GD 7-19 in the presence
or absence of ritonavir) as well as in rabbits (doses up to 1000 mg/kg/day
from GD 8-20 with darunavir alone)…
Cobicistat:
Cobicistat was administered orally to pregnant rats at doses up to 125
mg/kg/day on GD 6-17. Increases in post-implantation loss and decreased fetal
weights were observed at a maternal toxic dose of 125 mg/kg/day. No malformations
were noted at
doses up to 125 mg/kg/day. Systemic exposures (AUC) at
50 mg/kg/day in pregnant females were 1.6 times higher than human exposures at
the recommended daily dose of cobicistat.
In pregnant rabbits, cobicistat was administered orally
at doses up to 100 mg/kg/day during GD 7-20. No maternal or embryo/fetal
effects were noted at the highest dose of 100 mg/kg/day. Systemic exposures
(AUC) at 100 mg/kg/day were 3.8 times higher than human exposures at the
recommended daily dose of cobicistat.
In a pre/postnatal developmental study in rats,
cobicistat was administered orally at doses up to 75 mg/kg from GD 6 to
postnatal day 20, 21, or 22. At doses of 75 mg/kg/day, neither maternal nor
developmental toxicity was noted. Systemic exposures (AUC) at this dose were
1.2 times the human exposures at the recommended daily dose of cobicistat.
8.2 Lactation
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion;
additions and/or revisions are
underlined)
Risk Summary
…
There are no data on the presence of darunavir or
cobicistat in human milk, the effects on the breastfed infant, or the effects
on milk production. Darunavir and cobicistat are secreted into the milk of
lactating rats. Because of the potential for (1) HIV transmission (in
HIV- negative infants), (2) developing viral resistance (in HIV-positive
infants), and (3) serious adverse
reactions in breastfed infants, instruct mothers not to breastfeed if
they are receiving PREZCOBIX.
Data
Animal Data
Darunavir:
Studies in rats (with darunavir alone or with ritonavir) have demonstrated that
darunavir is secreted in the milk. In the rat pre- and postnatal development
study, a reduction in pup body weight gain was observed due to exposure of pups
to drug substances via milk. The maximal maternal plasma exposures achieved
with darunavir (up to 1000 mg/kg with ritonavir) were approximately 50% of
those obtained in humans at the recommended clinical dose of darunavir with
ritonavir.
Cobicistat:
During the pre/postnatal developmental toxicology study at doses up to 75
mg/kg/day, mean cobicistat milk to plasma ratio of up to 1.9 was measured 2
hours after administration to rats on lactation day 10.
8.4 Pediatric Use
(Additions and/or revisions are underlined)
Safety, effectiveness, and pharmacokinetics of PREZCOBIX in pediatric
patients less than 18 years of age have not been established. Darunavir, a
component of PREZCOBIX is not recommended in pediatric patients below 3
years of age because of toxicity and mortality observed in juvenile rats
dosed with darunavir.
Juvenile Animal
Toxicity Data
Darunavir: In
a juvenile toxicity study where rats were directly dosed with darunavir (up to
1000 mg/kg), deaths occurred from post-natal day 5 at plasma exposure levels
ranging from 0.1 to 1.0 of the human exposure levels. In a 4-week rat
toxicology study, when dosing was initiated on post-natal day 23 (the human
equivalent of 2 to 3 years of age), no deaths were observed with a plasma
exposure (in combination with ritonavir) 2 times the human plasma exposure
levels.
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