Labeling Approved for Prezista (darunavir)
On December 13, 2010, FDA approved new labeling for Prezista
(darunavir) to include a once daily dosing for treatment-experienced
adult patients with no darunavir resistance associated substitutions.
The major revisions to the package insert are summarized
below. Other minor changes to the package insert and patient
package insert were made for consistency.
Summary of Revisions:
A DOSAGE AND ADMINISTRATION Section 2.1 Treatment-Experienced
Adult patient was revised as follows:
The recommended oral dose for treatment-experienced adult
patients with no darunavir resistance associated substitutions
(V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V
and L89V) is 800 mg Prezista once daily with ritonavir 100
mg once daily and with food.
The recommended oral dose for treatment-experienced adult
patients with at least one darunavir resistance associated
substitution (V11I, V32I, L33F, I47V, I50V, I54L, I54M,
T74P, L76V, I84V and L89V) is 600 mg Prezista twice daily
taken with ritonavir 100 mg twice daily and with food.
For antiretroviral treatment experienced patients genotypic
testing is recommended. However, when genotypic testing
is not feasible, Prezista/ritonavir 600/100 mg twice daily
dosing is recommended.
The following statement was added to section 6: ADVERSE
The overall safety profile of PREZISTA/ritonavir 800/100
mg once daily and PREZISTA/ritonavir 600/100 mg twice daily
is based on clinical trials and post-marketing data, and
is consistent with the data presented below.
Section 12.3 Pharmacokinetics Table 8 was updated to include
the population pharmacokinetic estimates of darunavir from
Trial TMC114-C229 Prezista/ritonavir 800/100 mg once daily
and Prezista/ritonavir 600/100 mg twice daily.
Overall, darunavir exposures following darunavir/ritonavir
800/100 mg once daily in treatment experienced subjects
were consistent with those previously assessed in treatment-naive
Section 12.4 Microbiology was updated to include the results
TMC114-C229 as follows:
In the 48-week analysis of the Phase 3 Study TMC114-C229,
the number of virologic failures (including those who discontinued
before suppression after Week 4) was 26% (75/294) in the
group of subjects receiving Prezista/ritonavir 800/100 mg
once daily compared to 19% (56/296) of subjects receiving
Prezista/ritonavir 600/100 mg twice daily.
Examination of isolates from subjects who failed on Prezista/ritonavir
800/100 mg once daily and had post-baseline genotypes showed
that 8 subjects (8/60; 13%) had isolates that developed
IAS-USA defined PI resistance-associated substitutions compared
to 5 subjects (5/39; 13%) on Prezista/ritonavir 600/100
mg twice daily. Isolates from 2 subjects developed PI resistance
associated substitutions associated with decreased susceptibility
to darunavir; 1 subject isolate in the Prezista/ritonavir
800/100 mg once daily arm, developed substitutions V32I,
M46I, L76V and I84V associated with a 24-fold decreased
susceptibility to darunavir, and 1 subject isolate in the
Prezista/ritonavir 600/100 mg twice daily arm developed
substitutions L33F and I50V associated with a 40-fold decreased
susceptibility to darunavir. In the Prezista/ritonavir 800/100
mg once daily and Prezista/ritonavir 600/100 mg twice daily
groups, isolates from 7 (7/60, 12%) and 4 (4/42, 10%) virologic
failures, respectively, developed decreased susceptibility
to an NRTI included in the treatment regimen.
Section 14 CLINICAL STUDIES subsection 14.3 Treatment-Experiened
Adult Subjects was updated to include the results from Trial
TMC114-C229 as follows:
Study TMC114-C229 is a randomized, open label trial comparing
Prezista/ritonavir 800/100 mg once daily to Prezista/ritonavir
600/100 mg twice daily in treatment experienced HIV 1 infected
patients with screening genotype resistance test showing
no darunavir resistance associated substitutions (i.e. V11I,
V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V)
and a screening viral load of > 1,000 HIV 1 RNA copies/ml.
Both arms used an optimized background regimen consisting
of 2 NRTIs selected by the investigator.
HIV-1-infected subjects who were eligible for this trial
were on a highly active antiretroviral therapy regimen (HAART)
for at least 12 weeks. Virologic response was defined as
a confirmed plasma HIV-1 RNA viral load < 50 copies/mL.
Analyses included 590 subjects who had completed 48 weeks
of treatment or discontinued earlier.
Table 16 compares the demographic and baseline characteristics
between subjects in the Prezista/ritonavir 800/100 mg once
daily arm and subjects in the Prezista/ritonavir 600/100
mg twice daily arm in Study TMC114-C229. No imbalances between
the 2 arms were noted.
Virologic success (defined as HIV-1 RNA < 50 copies/mL)
at Week 48 was 69% for both Prezista/ritonavir 800/100 mg
once daily and Prezista/ritonavir 600/100 mg twice daily.
The mean increase from baseline in CD4+ cell counts was
comparable for both treatment arms (108 cells/mm3 and 112
cells/mm3 in the Prezista/ritonavir 800/100 mg once daily
arm and the Prezista/ritonavir 600/100 mg twice daily arm,
The revised labeling will be posted soon at Drugs@FDA.
Approves New Dosage Strength for Intelence
- New formulation reduces number of Intelence tablets taken
Titusville, N.J. -- January 3, 2011 -- The U.S. Food and
Drug Administration (FDA) approved a label update to include
a 200 mg formulation of Intelence (etravirine), a non-nucleoside
reverse transcriptase inhibitor (NNRTI) indicated for the
treatment of human immunodeficiency virus (HIV-1) in treatment-experienced
adults with resistance to an NNRTI and other antiretroviral
The recommended oral dose of Intelence tablets is 200 mg
(one 200 mg tablet or two 100 mg tablets) taken twice daily
following a meal. The new 200 mg product formulation is
expected to launch in the U.S. later this month, and the
100 mg tablet will remain available. Patients who are unable
to swallow Intelence tablets whole may disperse the tablets
in a glass of water.
granted accelerated approval to Intelence in January 2008,
and it has since been approved in more than 65 countries.
Intelence received traditional FDA approval in November
2009, based on 48-week data from the DUET-1 and DUET-2 studies,
and is currently marketed in the U.S. by Tibotec Therapeutics,
a division of Centocor Ortho Biotech Products, L.P.
Intelence, in combination with other antiretroviral agents,
is indicated for the treatment of HIV-1 infection in ARV
treatment-experienced adult patients who have evidence of
viral replication and HIV-1 strains resistant to an NNRTI
and other ARV agents. This indication is based on Week 48
analyses from two randomized, double-blind, placebo-controlled
trials of Intelence. Both studies were conducted in clinically
advanced, three-class ARV (NNRTI, N[t]RTI, PI) treatment-experienced
The following points should be considered when initiating
therapy with Intelence:
history and, when available, resistance testing, should
guide the use of Intelence.
The use of other active ARV agents with Intelence is associated
with an increased likelihood of treatment response.
In patients who have experienced virologic failure on an
NNRTI-containing regimen, do not use Intelence in combination
with only N[t]RTIs.
The risks and benefits of Intelence have not been established
in pediatric patients or in treatment-naive adult patients.
the DUET studies
The DUET studies, identical in design and conducted across
the Americas, Australia, Canada, Europe and Thailand, examined
the use of Intelence in combination with other ARV agents
in adult treatment-experienced HIV-1 patients with documented
resistance to NNRTIs and protease inhibitors (PIs). Participants
in the DUET studies were randomized to receive Intelence
200 mg twice daily or placebo, each given in addition to
a background regimen (BR). For all patients, the BR included
darunavir/ritonavir, plus at least two investigator-selected
antiretroviral drugs (N(t)RTIs with or without enfuvirtide).
Important Safety Information
Intelence does not cure HIV infection or AIDS, and does
not prevent passing HIV to others.
Warnings & Precautions
Skin and Hypersensitivity Reactions:
Severe, potentially life-threatening, and fatal skin reactions
have been reported in patients taking Intelence. These include
cases of Stevens-Johnson syndrome, toxic epidermal necrolysis,
and erythema multiforme
Hypersensitivity reactions have also been reported and were
characterized by rash, constitutional findings, and sometimes
organ dysfunction, including hepatic failure
the DUET studies, Grade 3 and 4 rashes were reported in
1.3% of patients receiving Intelence compared to 0.2% of
patients in the placebo arm. Discontinuation rate due to
rash was 2.2% in patients taking Intelence. Rash occurred
most commonly during the first 6 weeks of therapy.
Discontinue Intelence immediately if signs or symptoms of
severe skin reactions or hypersensitivity reactions develop
(including, but not limited to, severe rash or rash accompanied
by fever, general malaise, fatigue, muscle or joint aches,
blisters, oral lesions, conjunctivitis, facial edema, hepatitis,
Monitor clinical status including liver transaminases, and
initiate appropriate therapy
Delay in stopping Intelence treatment after the onset of
severe rash may result in a life-threatening reaction
Fat Redistribution: Redistribution and/or accumulation of
body fat have been observed in patients receiving antiretroviral
(ARV) therapy. The causal relationship, mechanism, and long-term
consequences of these events have not been established
Immune Reconstitution Syndrome: has been reported in patients
treated with ARV therapy, including Intelence
in Specific Populations
Impairment: Intelence should be used with caution in patients
with severe hepatic impairment (Child-Pugh Class C) as pharmacokinetics
of Intelence have not been evaluated in these patients
Pregnancy Category B: Intelence should be used during pregnancy
only if the potential benefit justifies the potential risk.
No adequate and well-controlled studies have been conducted
in pregnant women
most common adverse drug reactions (> or = 2%) of at
least moderate intensity (> or = Grade 2) reported in
patients taking Intelence and that occurred at a higher
rate compared with placebo were rash (10% vs 3%) and peripheral
neuropathy (4% vs 2%)
should not be coadministered with the following ARVs: tipranavir/ritonavir,
fosamprenavir/ritonavir, atazanavir/ritonavir, full-dose
ritonavir (600 mg bid), protease inhibitors administered
without low-dose ritonavir, and other NNRTIs
Intelence should not be co-administered with carbamazepine,
phenobarbital, phenytoin, rifampin, rifapentine, rifabutin
(when part of a regimen containing protease inhibitor/ritonavir)
or products containing St. John's wort (Hypericum perforatum)
Coadministration of Intelence with other agents such as
substrates, inhibitors, or inducers of CYP3A, CYP2C9, CYP2C19,
and/or P-glycoprotein may alter the therapeutic effect or
adverse reaction profile of Intelence or the coadministered
is not a complete list of potential drug interactions
You are encouraged to report negative side effects of prescription
drugs to the FDA. Visit www.fda.gov/medwatch,
or call 1-800-FDA-1088
Please see full Prescribing Information for more details.
Full prescribing information is also available at www.INTELENCE-info.com.
About Tibotec Therapeutics
Tibotec Therapeutics, a division of Centocor Ortho Biotech
Products, L.P., headquartered in Titusville, N.J., is dedicated
to delivering innovative virology therapeutics that help
healthcare professionals address serious unmet needs in
people living with HIV. For more information, see www.tibotec.com.
R Klein and K Struble, Food and Drug Administration. New labeling
approved for Prezista (darunavir). HIV/AIDS Update. December
R Klein and K Struble, Food and Drug Administration. New Intelence
(etravirine) dosage approved. HIV/AIDS Update. December 24,
Tibotec. FDA approves new dosage strength for Intelence. Press
release. January 3, 2010.