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The Stribild (elvitegravir, cobicistat, emtrictiabine,
tenofovir disoproxil fumarate) tablet label was revised to expand the patient
population to include pediatric patients 12 years of age and older weighting at
least 35 kg based upon the week 48 results from Study GS-US-236-0112. The
WARNINGS and PRECAUTIONS, New Onset or Worsening Renal Impairment section was
updated to include serum creatinine and serum phosphorus as part of renal
function testing prior to and during administration of Stribild. The Bone Loss
and Mineralization Defects subsection was updated with information about the
effects of tenofovir DF on bone mineral density in pediatric and adolescent
patients. The WARNINGS and PRECAUTIONS was also revised to emphasize severe
acute exacerbations of Hepatitis B in coinfected patients. Additionally USE IN
SPECIFIC POPULATIONS section of the labeling was reformatted for sections 8.1
and 8.2 according to the Pregnancy and Lactation Labeling Rule.
The major changes are outlined below.
Indications
and Usage was updated to include pediatric patients as follows
STRIBILD® is indicated as a complete regimen for the
treatment of HIV-1 infection in adults and pediatric patients 12 years of age
and older weighing at least 35 kg who have no antiretroviral treatment history
or to replace the current antiretroviral regimen in those who are virologically
suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral
regimen for at least 6 months with no history of treatment failure and no known
substitutions associated with resistance to the individual components of
STRIBILD [see Clinical Studies (14)].
The DOSAGE AND
ADMINISTRATION
section has
been edited and reformatted to include the new indication in pediatric patients
and
updated hepatic and renal testing language.
2 DOSAGE
AND ADMINISTRATION
2.1 Testing
Prior to Initiation and During Treatment with STRIBILD
Prior to initiation of STRIBILD, patients should be
tested for hepatitis B virus infection [see Warnings and Precautions (5.2)].
It is recommended that serum creatinine, serum
phosphorous, estimated creatinine clearance, urine glucose, and urine protein
should be assessed before initiating STRIBILD and during therapy in all
patients as clinically appropriate [see Warnings and Precautions (5.3)].
2.2 Recommended
Dosage
STRIBILD is a four-drug fixed dose combination product
containing 150 mg of elvitegravir, 150 of cobicistat, 200 mg of emtricitabine,
and 300 mg of tenofovir DF. The recommended dosage of STRIBILD is one tablet
taken orally once daily with food in adults and pediatric patients 12 years of
age and older with a body weight at least 35 kg (at least 77 lbs) and
creatinine clearance greater than or equal to 70 mL per minute [see Clinical
Pharmacology (12.3)].
2.3 Dosage
Adjustment in Patients with Renal Impairment
No data are available to make dose recommendations for
pediatric patients with renal impairment.
In the WARNINGS AND PRECAUTIONS section, the subsection 5.2 has
been edited to emphasize severe acute exacerbations of Hepatitis B in coinfected patients.
5.2 Severe
Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV
All patients with HIV-1 should be tested for the presence
of hepatitis B virus (HBV) before initiating antiretroviral therapy [see Dosage
and Administration (2.1)]. STRIBILD is not approved for the treatment of
chronic HBV infection, and the safety and efficacy of STRIBILD have not been
established in patients coinfected with HIV-1 and HBV.
Severe acute exacerbations of hepatitis B (e.g., liver
decompensated and liver failure) have been reported in patients who are
coinfected with HBV and HIV-1 and have discontinued emtricitabine or tenofovir
DF, two of the components of STRIBILD. Patients who are coinfected with HIV-1
and HBV should be closely monitored with both clinical and laboratory follow-up
for at least several months after stopping treatment with STRIBILD. If
appropriate, initiation of anti-hepatitis B therapy may be warranted,
especially in patients with advanced liver disease or cirrhosis, since
post-treatment exacerbation of hepatitis may lead to hepatic decompensation and
liver failure.
In
subsection 5.3 New Onset or Worsening Renal Impairment, serum creatinine and
serum phosphorus have been added to the renal function testing to be assessed
before initiating STRIBILD.
It is recommended that serum creatinine, serum
phosphorus, estimated creatinine clearance, urine glucose, and urine protein be
assessed before initiating STRIBILD and during therapy in all patients as
clinically appropriate. Initiation of STRIBILD in patients with estimated
creatinine clearance below 70 mL per minute is not recommended [see Dosage and
Administration (2.1)].
Subsection 5.5
has
updated with new clinical information from recent pediatric
trials.
Clinical trials evaluating tenofovir DF in pediatric and adolescent subjects were conducted. Under normal circumstances, BMD increases rapidly in
pediatric patients. In HIV-1-infected subjects aged 2 years to
less than 18 years, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the tenofovir DF-treated HIV-1-infected pediatric subjects as compared to the control groups. In all pediatric trials, skeletal
growth (height) appeared to be unaffected. For more information, please consult the tenofovir DF prescribing information.
Section
6 Adverse Reactions was updated to include data in pediatric subjects as
follows.
Clinical Trials in Pediatric Subjects
The safety of STRIBILD in 50 HIV-1-infected,
treatment-naïve pediatric subjects aged 12 to less than 18 years and weighing
at least 35 kg (77 lbs) was evaluated through 48 weeks in an open-label
clinical trial (Study 112) [see Clinical Studies (14.4)]. In this study, the
safety profile of STRIBILD was similar to that in adults. Twenty-two subjects
(44%) had treatment-emergent proteinuria (Grades 1−2). One subject met
laboratory criteria for proximal renal tubulopathy, evidenced by sustained
proteinuria and normoglycemic glycosuria beginning at Week 32. The subject
continued to receive STRIBILD and was ultimately lost to follow-up.
Among the 50 pediatric subjects receiving STRIBILD for 48
weeks, mean BMD increased from baseline to Week 48, +0.68% at the lumbar spine
and +0.77% for total body less head. Mean changes from baseline BMD Z-scores
(height-age adjusted) to Week 48 were −0.09 for lumbar spine and −0.12 for
total body less head. At Week 48, 7 STRIBILD subjects had significant (greater
than or equal to 4%) lumbar spine BMD loss and 2 had significant total body
less head BMD loss.
In Section 12, CLINICAL PHARMACOLOGY, pediatric PK data
has
been added in
subsection 12.3 Pharmacokinetics.
Pediatric Patients
Exposures (AUC) of elvitegravir and tenofovir in 14 pediatric subjects aged 12 to
less than 18 years who received STRIBILD in Study 112 were increased by 30% and 37%, respectively, compared with exposures achieved in adults following administration of STRIBILD, but were deemed acceptable based on the overall safety
profile of these agents and exposure-safety assessments. The other components
of STRIBILD had similar exposures in adolescents compared with adults [see
Use
in Specific Populations (8.4)].
Section 14, CLINICAL STUDIES,
has
been edited and updated with pediatric study trial information.
14.4 Clinical
Trial Results in HIV-1Treatment-Naïve Adolescent Subjects Aged 12 to Less than
18 Years
In Study 112,
the efficacy, safety, and pharmacokinetics of STRIBILD were evaluated in a
single group, open-label trial in HIV-1-infected treatment-naïve adolescents
aged 12 to less than 18 years of age and weighing at least 35 kg (77 lbs)
(N=50). Mean age was 15 years (range, 12−17); 70% were male, 68% black, and 28%
Asian. At baseline, mean plasma HIV-1 RNA was 4.60 log10 copies per
mL (range, 3.18−5.73), mean CD4+ cell count was 399 cells per mm3
(range, 133−734), and mean CD4+ percentage was 20.9% (range, 4.5%−41.1%).
Twenty percent had baseline plasma HIV-1 RNA >100,000 copies per mL.
At Week 48, 44
of 50 (88%) adolescent patients treated with STRIBILD achieved HIV-1 RNA <50
copies per mL and 4 had HIV-1 RNA ≥50 copies per
mL; 1 patient discontinued study drug; 1 had no virologic data at Week 48. The
mean decrease from baseline in HIV-1 RNA was −3.16 log10 copies per
mL; mean increase from baseline in CD4+ cell count was 229 cells per mm3.
No emergent resistance to STRIBILD was detected through Week 48.
The updated label will soon be available drugs@fda or DailyMed
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