Drug Safety-related Labeling Changes (SrLC)

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STRIBILD (NDA-203100)

(COBICISTAT; ELVITEGRAVIR; EMTRICITABINE; TENOFOVIR DISOPROXIL FUMARATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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08/21/2020 (SUPPL-35)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions

Additions and/or revisions underlined:

• Loss of therapeutic effect of STRIBILD and possible development of resistance.

• Clinically significant adverse reactions, potentially leading to severe, life- threatening, or fatal events, from greater exposures of concomitant drugs metabolized by CYP3A.

• Loss of therapeutic effect of concomitant drugs that utilize CYP3A to form active metabolites.

5.6 Immune Reconstitution Syndrome

Additions and/or revisions 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 treatment.

7 Drug Interactions

7.2 Potential for STRIBILD to Affect Other Drugs

Additions and/or revisions underlined:

… Thus, coadministration of STRIBILD with drugs that are primarily metabolized by CYP3A or CYP2D6, or are substrates of P-gp, BCRP, OATP1B1, or OATP1B3, may result in increased plasma concentrations of such drugs.

Coadministration of STRIBILD with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentration of these active metabolite(s) (Table 5) …

7.6 Drugs without Clinically Significant Interactions with STRIBILD

Additions and/or revisions underlined:

Based on drug interaction studies conducted with the components of STRIBILD, no clinically significant drug interactions have been observed or are expected when STRIBILD is combined with the following drugs: famciclovir, famotidine, methadone, omeprazole, prasugrel (active metabolite), and sertraline.

8 Use in Specific Populations

8.1 Pregnancy

Risk Summary

Additions and/or revisions underlined:

… Available data from the APR show no significant difference in the overall risk of major birth defects for elvitegravir, cobicistat, emtricitabine, or TDF 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) …

Data

Human Data

… Prospective reports from the APR of overall major birth defects in pregnancies exposed to the components of STRIBILD 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. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation.

Elvitegravir: Based on prospective reports to the APR of exposures to elvitegravir- containing regimens during pregnancy resulting in live births (including over 300 exposed in the first trimester and over 60 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.4% (95% CI: 1.7% to 6.0%) and 1.5% (95% CI: 0% to 7.9%) following first and second/third trimester exposure, respectively, to elvitegravir-containing regimens.

Cobicistat: Based on prospective reports to the APR of exposures to cobicistat- containing regimens during pregnancy resulting in live births (including over 400 exposed in the first trimester and over 80 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.9% (95% CI: 2.2% to 6.3%) and 1.2% (95% CI: 0.0% to 6.5%) following first and second/third trimester exposure, respectively, to cobicistat-containing regimens.

Emtricitabine: Based on prospective reports to the APR of exposures to emtricitabine- containing regimens during pregnancy resulting in live births (including over 3,600 exposed in the first trimester and over 1,400 exposed in the second/third trimester), the prevalence of birth defects in live births was 2.6% (95% CI: 2.1% to 3.2%) and 2.4% (95% CI: 1.6% to 3.3%) following first and second/third trimester exposure, respectively, to emtricitabine-containing regimens.

Tenofovir DF: Based on prospective reports to the APR of exposures to TDF-containing regimens during pregnancy resulting in live births (including over 4,200 exposed in the first trimester and over 1,800 exposed in the second/third trimester), the prevalence of birth defects in live births was 2.4% (95% CI: 1.9% to 2.9%) and 2.4% (95% CI: 1.8% to 3.2%) following first and second/third trimester exposure, respectively, to TDF- containing regimens.

02/06/2019 (SUPPL-34)

Approved Drug Label (PDF)

7 Drug Interactions

7.5 Established and Other Potentially Significant Interactions

(addition of the following text  (underlined) in Table 5 under atorvastatin)

Initiate atorvastatin with the lowest starting dose of atorvastatin and titrate carefully while monitoring for safety (e.g., myopathy). Do not exceed a dosage of atorvastatin 20 mg daily.

11/02/2018 (SUPPL-33)

Approved Drug Label (PDF)

4 Contraindications

4 Contraindications

(Additions and/or revisions are underlined)

• …

• Lipid-modifying Agents: lomitapide, lovastatin, simvastatin

• Phosphodiesterase-5 (PDE-5) Inhibitor: sildenafil when administered as Revatio® for the treatment of pulmonary arterial hypertension

• Sedative/hypnotics: triazolam, orally administered midazolam

• …

5 Warnings and Precautions

5.1 Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV

(Additions and/or revisions are underlined)

All patients with HIV-1 should be tested for the presence of hepatitis B virus (HBV) before initiating antiretroviral therapy.

 

Severe acute exacerbations of hepatitis B (e.g., liver decompensated and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued emtricitabine or TDF, two of the components of STRIBILD. …

6 Adverse Reactions

6.1 Clinical Trials Experience

(Table 1 has been revised; please refer to label)

7 Drug Interactions

7.5 Established and Other Potentially Significant Interactions

(Table 5 has been revised; please refer to label)

 

7.6         Drugs without Clinically Significant Interactions with STRIBILD

 

(Additions and/or revisions are underlined)

Based on drug interaction studies conducted with the components of STRIBILD, no clinically significant drug interactions have been observed when STRIBILD is combined with the following drugs: famciclovir, famotidine, methadone, omeprazole, and sertraline.

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 women exposed to STRIBILD during pregnancy.  Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary

STRIBILD is not recommended during pregnancy.  A literature report evaluating the pharmacokinetics (PK) of antiretrovirals during pregnancy demonstrated substantially lower exposures of elvitegravir and cobicistat in the second and third trimesters .

Prospective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects or miscarriage. However, elvitegravir, cobicistat, emtricitabine, and TDF use during pregnancy have been evaluated in a limited number of individuals as reported to the APR. Available data from the APR show no increase in the overall risk of major birth defects for cobicistat, emtricitabine or TDF 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 number of exposures to elvitegravir is insufficient to make a risk assessment compared to a reference population (see Data). The rate of miscarriage is not reported in the APR. In the U.S. general population, the estimated background risk of miscarriage in clinically recognized pregnancies is 15?20%.

In animal studies, no adverse developmental effects were observed when the components of STRIBILD were administered separately during the period of organogenesis at exposures up to 23 and 0.2 times (rats and rabbits, respectively, elvitegravir), 1.8 and 4.3 times (rats and rabbits, respectively, cobicistat), and 60 and 120 times (mice and rabbits, respectively, emtricitabine) the exposure at the recommended daily dose of these components in STRIBILD, and at 14 and 19 times (rats and rabbits, respectively, TDF) the human dose based on body surface area comparisons [see Data]. Likewise, no adverse developmental effects were seen when elvitegravir or cobicistat was administered to rats through lactation at exposures up to 18 times or 1.2 times, respectively, the exposure at the recommended daily therapeutic dose, and when emtricitabine was administered to mice through lactation at exposures up to approximately 60 times the exposure at the recommended daily therapeutic dose. No adverse effects were observed in the offspring of rats when TDF was administered through lactation at tenofovir exposures of approximately 2.7 times the exposure at the recommended daily dosage of STRIBILD.

 

Data

Human Data

A prospective study, reported in the literature, enrolled 30 pregnant women living with HIV who were receiving elvitegravir and cobicistat-based regimens in the second or third trimesters of pregnancy and through 6 to 12 weeks postpartum to evaluate the pharmacokinetics (PK) of antiretrovirals during pregnancy. Twenty-eight women completed the study through the postpartum period. Paired pregnancy/postpartum PK data were available from 14 and 24 women for the second and third trimesters, respectively. Exposures of elvitegravir and cobicistat were substantially lower during the second and third trimesters compared to postpartum. The proportion of pregnant women who were virologically suppressed was 77% in the second trimester, 92% in the third trimester, and 76% postpartum. No correlation was observed between viral suppression and elvitegravir exposure. HIV status was also assessed for infants: 25 were uninfected, 2 had indeterminate status, and no information was available for 3 infants.

Prospective reports from the APR of overall major birth defects in pregnancies exposed to the components of STRIBILD 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.

Elvitegravir: The APR has received prospective reports of 5 birth defects among 180 first trimester exposures to elvitegravir-containing regimens during pregnancy resulting in live births. No birth defects were reported among 52 exposures during the second/third trimester. The number of exposures is insufficient to make a risk assessment compared to a reference population.

Cobicistat: Based on prospective reports to the APR of 204 first trimester exposures to cobicistat- containing regimens during pregnancy, there was no increase in overall major birth defects with cobicistat compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.5% (95% CI: 0.8% to 5.6%) with first trimester exposure to cobicistat-containing regimens; the 58 second/third trimester cobicistat exposures reported to the APR are insufficient to make a risk assessment.

Emtricitabine: Based on prospective reports to the APR of exposures to emtricitabine-containing regimens during pregnancy resulting in live births (including over 2,700 exposed in the first trimester and over 1,200 exposed in the second/third trimester), there was no increase in overall major birth defects with emtricitabine compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.4% (95% CI: 1.9% to 3.1%) with first trimester exposure to emtricitabine-containing regimens and 2.3% (95% CI: 1.5% to 3.3%) with second/third trimester exposure to emtricitabine-containing regimens.

Tenofovir DF:  Based on prospective reports to the APR of exposures to TDF-containing regimens during pregnancy resulting in live births (including over 3,500 exposed in the first trimester and over 1,500 exposed in the second/third trimester), there was no increase in overall major birth defects with TDF compared with the background birth defect rate of 2.7% in theU.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.3% (95% CI: 1.8% to 2.9%) with first trimester exposure, and 2.2% (95% CI: 1.6% to 3.1%) with the second/third trimester exposure to TDF-containing regimens.

…

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 STRIBILD is not recommended during pregnancy and to alert their healthcare provider if they become pregnant while taking STRIBILD. Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant individuals exposed to STRIBILD.

 

Lactation

Instruct mothers with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk.

…

Other

Patient Information

(Additions and/or revisions are underlined)

 …

 

What should I tell my healthcare provider before taking STRIBILD?

Before taking STRIBILD, tell your healthcare provider about all of your medical conditions, including if you:

• have liver problems including hepatitis B infection

• have kidney problems

• have bone problems

• are pregnant or plan to become pregnant

  • It is not known if STRIBILD can harm your unborn baby.

  • STRIBILD should not be used during pregnancy because you may not have enough STRIBILD in your body during pregnancy.

  • Tell your healthcare provider if you become pregnant while taking STRIBILD. Your healthcare provider may prescribe different medicines if you become pregnant while taking STRIBILD.

Pregnancy Registry. There is a pregnancy registry for women who take antiviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk with your healthcare provider about how you can take part in this registry.

…

08/07/2018 (SUPPL-32)

Approved Drug Label (PDF)

4 Contraindications

Contraindications

(Newly added subsection)

•  Alpha 1-adrenoreceptor antagonist: alfuzosin

• Anticonvulsants: carbamazepine, phenobarbital, phenytoin

• Antimycobacterial: rifampin

• Antipsychotics: lurasidone, pimozide

• Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine

• GI Motility Agent: cisapride

• Herbal Products: St. John’s wort (Hypericum perforatum)

• HMG-CoA Reductase Inhibitors: lovastatin, simvastatin

• Phosphodiesterase-5 (PDE-5) Inhibitor: sildenafil when administered as Revatio® for the treatment of pulmonary arterial hypertension

• Sedative/hypnotics: triazolam, orally administered midazolam

5 Warnings and Precautions

5.2 New Onset or Worsening Renal Impairment

(Additions are underlined)

…

Prior to initiation and during use of STRIBILD, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Discontinue STRIBILD in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. Initiation of STRIBILD in patients with estimated creatinine clearance below 70 mL per minute is not recommended.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Table has been revised; please refer to label)

7 Drug Interactions

7.5 Established and Other Potentially Significant Interactions

(Table has been revised; please refer to label)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

(Format changed, please refer to label)

08/30/2017 (SUPPL-30)

Approved Drug Label (PDF)

7 Drug Interactions

7.5 Established and Other Potentially Significant Interactions

Table 6 Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction

HMG-CoA Reductase Inhibitors:

Clinical Comment addition/revision underlined:

… while monitoring for safety (e.g., myopathy). Do not exceed a dosage of atorvastatin 20 mg daily.

Hormonal Contraceptives:

Additional drug name:

drospirenone/ethinyl estradiol

Effect on Concentration:

Increased drospirenone

Clinical Comment added:

Plasma concentrations of drospirenone may be increased when coadministered with cobicistat- containing products. Clinical monitoring is recommended due to the potential for hyperkalemia.

or oral contraceptives containing progestogens other than drospirenone or norgestimate has not been studied.

7.6 Drugs without Clinically Significant Interactions with STRIBILD

Additions and/or revisions underlined:

… no clinically significant drug interactions have been either observed or are expected when STRIBILD is combined with the following drugs: entecavir, famciclovir, H2 receptor antagonists, methadone, proton pump inhibitors, ribavirin, and sertraline.

05/04/2017 (SUPPL-29)

Approved Drug Label (PDF)

7 Drug Interactions

7.5 Established and Other Potentially Significant Interactions

(extensive additions  to Table 6, please refer to label)

7.6 Drugs without Clinically Significant Interactions with STRIBILD

(additions underlined)

Based on drug interaction studies conducted with the components of STRIBILD, no clinically significant drug interactions have been either observed or are expected when STRIBILD is combined with the following drugs: beclomethasone, entecavir, famciclovir, H2 receptor antagonists, methadone, prednisolone, proton pump inhibitors, and ribavirin.

04/07/2017 (SUPPL-28)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Lactic Acidosis/Severe Hepatomegaly with Steatosis

(Additions and/or revisions are underlined)

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir DF and emtricitabine, components of STRIBILD, alone or in combination with other antiretrovirals…

7 Drug Interactions

7.5 Established and Other Potentially Significant Interactions

Table 6 Established and Other Potentially Significant (superscript a) Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction

(Table has been revised; please refer to label)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV

Inform patients that severe acute exacerbations of hepatitis B  have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued emtricitabine or tenofovir DF.

Patient Information

(Additions and/or revisions are underlined)

What are the possible side effects of STRIBILD?

STRIBILD may cause the following serious side effects, including:

• Too much lactic acid in your blood (lactic acidosis). Too much lactic acid is a serious but rare medical emergency that can lead to death. Tell your healthcare provider right away if you get these symptoms: weakness or being more tired than usual, unusual muscle pain, being short of breath or fast breathing, stomach pain with nausea and vomiting, cold or blue hands and feet, feel dizzy or lightheaded, or a fast or abnormal heartbeat.
• Severe liver problems. In rare cases, severe liver problems can happen that can lead to death. Tell your healthcare provider right away if you get these symptoms: skin or the white part of your eyes turns yellow, dark “tea- colored” urine, light-colored stools, loss of appetite for several days or longer, nausea, or stomach-area pain.

01/27/2017 (SUPPL-25)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV

(Additions and/or revisions are underlined; revised subsection title)

All patients with HIV-1 should be tested for the presence of hepatitis B virus (HBV) before initiating antiretroviral therapy.

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.

5.3 New Onset or Worsening Renal Impairment

(Additions and/or revisions are underlined)

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.

5.5 Bone Loss and Mineralization Defects

(Additions and/or revisions are underlined; revised subsection title)

Bone Mineral Density

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.

 

…Assessment of BMD should be considered for HIV-1-infected adult and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss…

6 Adverse Reactions

(Additions and/or revisions are underlined)

The following adverse reactions are discussed in other sections of the labeling:

• Severe Acute Exacerbations of Hepatitis B in Patients Coinfected with HIV-1 and HBV

• Bone Loss and Mineralization Defects

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

Clinical Trials in HIV-1-Infected Adult Subjects with No Antiretroviral Treatment History

The safety assessment of STRIBILD is based on the Week-144 pooled data from 1408 subjects in two randomized, double-blind, active-controlled clinical trials, Study 102 and Study 103…

 

Table 2 Adverse Reactionsa (All Grades) Reported in Greater Than or Equal to 5% of Adult Subjects in Any Treatment Arm in Studies 102 and 103 (Week-144 Analysis)

 

Clinical Trials in Virologically Suppressed HIV-1-Infected Adult Subjects

No new adverse reactions to STRIBILD through Week 48 were identified in 584 virologically stably suppressed adult subjects switching to STRIBILD from a regimen containing a RTV-boosted protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI)…

 

Clinical Trials of the Components of STRIBILD in Adult Subjects

Emtricitabine and Tenofovir Disoproxil Fumarate: In addition to the adverse reactions observed with STRIBILD, the following adverse reactions occurred in at least 5% of treatment-experienced or treatment-naïve subjects…

 

Laboratory Abnormalities:

Table 3 Laboratory Abnormalities (Grades 3?4) Reported in Greater Than or Equal to 2% of Adult Subjects Receiving STRIBILD in Studies 102 and 103 (Week-144 Analysis)

 

Table 5 Lipid Values, Mean Change from Baseline at Week 144 in Adult Subjects Receiving STRIBILD or Comparator in Studies 102 and 103

 

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). 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.

7 Drug Interactions

7.1 Not Recommended with Other Antiretroviral Medications

(Revised subsection title)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion) (Extensive changes; please refer to label)

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

Risk Summary

…Based on limited published data, emtricitabine and tenofovir have been shown to be present in human breast milk. It is not known whether elvitegravir or cobicistat are present in human breast milk, while elvitegravir and cobicistat have been shown to be present in rat milk.

It is not known if the components of STRIBILD affect milk production or have effects on the breastfed child. Because of the potential for: (1) HIV transmission (in HIV-negative infants); (2) developing viral resistance (in HIV-positive infants); and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving STRIBILD.

 

Animal Data

Elvitegravir: During the prenatal and postnatal developmental toxicology study at doses up to 2000 mg/kg/day mean elvitegravir milk to plasma ratio of 0.1 was measured 30 minutes after administration to rats on lactation day 14.

Cobicistat: During the prenatal and 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)

The pharmacokinetics, safety, and virologic and immunologic responses were evaluated in 50 treatment-naïve, HIV-1-infected subjects aged 12 to less than 18 years weighing at least 35 kg (77 lbs) receiving STRIBILD through 48 weeks in an open-label trial (Study 112). The safety and efficacy of STRIBILD in these subjects was similar to that in antiretroviral treatment-naïve adults.

Safety and effectiveness of STRIBILD in pediatric patients less than 12 years of age or weighing less than 35 kg (77 lbs) have not been established.

8.6 Renal Impairment

(Additions and/or revisions are underlined)

No data are available to make dose recommendations for pediatric patients with renal impairment.

 

Clinical Trials in Adult Subjects with Mild to Moderate Renal Impairment

In Study 118, 33 HIV-1-infected treatment-naïve subjects with mild to moderate renal impairment…

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17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Drug Interactions

Advise patients that STRIBILD may interact with many drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John’s wort.

 

Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV

Inform patients that hepatitis B testing is recommended prior to initiating antiretroviral therapy…

 

Bone Loss and Mineralization Defects

Inform patients that decreases in bone mineral density have been observed with the use of STRIBILD…

 

Missed Dosage

Inform patients that it is important to take STRIBILD on a regular dosing schedule with food and to avoid missing doses as it can result in development of resistance.

 

Pregnancy Registry

Inform patients thatthere is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant women exposed to STRIBILD.

 

Lactation

Instruct women 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)

What is STRIBILD?

STRIBILD is a prescription medicine that is used without other antiretroviral medicines to treat Human Immunodeficiency Virus-1 (HIV-1) in people 12 years of age and older:

 

It is not known if STRIBILD is safe and effective in children under 12 years of age or who weigh less than 77 lbs.

09/15/2016 (SUPPL-24)

Approved Drug Label (PDF)

4 Contraindications

Table 1- Drugs that are Contraindicated with STRIBILD

Drug Class : Antipsychotics (added)

  Drugs within Class that are Contraindicated with STRIBILD :

 

      Lurasidone

Clinical Comment  :Potential for serious and/or life-threatening reactions.

 

 

     Pimozide

Clinical Comment : Potential for serious and/or life-threatening reactions such as arrhythmias.

7 Drug Interactions

 

 

7.5 Established and Other Potentially Significant Interactions

 

Table 6

Established and Other Potentially Significant Drug Interactions: Alterationin Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction

Concomitant Drug Class: Drug Name

      Antipsychotics: e.g.(following drugs added)

perphenazine

risperidone

thioridazine

 

Effect on Concentration: Antipsychotic concentration will increase.

Clinical Comment : A decrease in the dose of antipsychotics that are metabolized by CYP3A4 or CYP2D6 may be needed when coadministered with STRIBILD.

 

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Who should not take STRIBILD?

Do not take STRIBILD if you also take a medicine that contains:

·       lurasidone (LATUDA®) (added)

02/19/2016 (SUPPL-21)

Approved Drug Label (PDF)

7 Drug Interactions

Antipsychotics:

quetiapine

• Initiation of STRIBILD in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposure. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.
• Initiation of quetiapine in patients taking STRIBILD: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine

Hepatitis C Antiviral Agents:

ledipasvir/sofosbuvir

• The safety of increased tenofovir concentrations in the setti