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Stribild (Elvitegravir, Cobicistat, Emtrictiabine, Tenofovir Disoproxil Fumarate) Tablet Label Revised to Expand the Patient Population

January 31, 2017

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 weighing 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.

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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-naive 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-Naive 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-naive 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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This article was provided by U.S. Food and Drug Administration. Visit the FDA's website to find out more about their activities and publications.
 

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