Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

TYBOST (NDA-203094)

(COBICISTAT)

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

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06/20/2025 (SUPPL-17)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

. . .

Adverse Reactions from Clinical Trials Experience in Pediatric Participants

The safety of TYBOST was evaluated in an open-label clinical trial (Trial 128) of pediatric participants with HIV-1 administered TYBOST-boosted atazanavir or darunavir plus two nucleoside reverse transcriptase inhibitors; this study included 22 virologically- suppressed participants between the ages of 12 to less than 18 years (weighing greater than or equal to 35 kg) administered atazanavir (N=14) or darunavir (N=7) through Week 48; 9 virologically- suppressed pediatric participants between the ages of 6 to less than 12 years weighing at least 25 kg to less than 40 kg administered darunavir (N=9) through Week 48; and 11 virologically-suppressed participants at least 2 years of age (weighing greater than or equal to 14 kg to <25 kg) administered darunavir through Week 48 [see Drug Interactions (7.3), Use in Specific Populations (8.4), Clinical Studies (14.2)]. In this trial, the safety profile of TYBOST was similar to that in adults.

7 Drug Interactions

7.3 Established and Other Potentially Significant Interactions

. . .

Table 7 Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction

Extensive changes to table; please refer to label for complete information.

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors fetal outcomes in individuals exposed to TYBOST during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) 1-800-258-4263.

. . .

Data

Human Data

. . .

The APR has received prospective reports of live births following exposure to cobicistat- containing regimens during pregnancy, including over 600 exposures in the first trimester and over 90 exposures in the second/third trimester. The prevalence of birth defects in live births was 3.5% (95% CI: 2.2% to 5.3%) and 3.2% (95% CI: 0.7% to 9.1%) following first trimester and second/third trimester exposure, respectively, to cobicistat-containing regimens. 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.

. . .

8.2 Lactation

Additions and/or revisions underlined:

Risk Summary

There is no information regarding the presence of cobicistat in human milk, the effects on the breastfed infant, or the effects on milk production. Cobicistat is present in rat milk (see Data).

Potential risks of breastfeeding include: (1) HIV-1 transmission to HIV-1–negative infants; (2) developing viral resistance in HIV-1–positive infants; and (3) adverse reactions in a breastfed infant similar to those seen in adults.

Animal Data

During the prenatal and postnatal development 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 underlined:

The safety and effectiveness of TYBOST coadministered with atazanavir or darunavir and two nucleoside reverse transcriptase inhibitors for the treatment of HIV-1 infection have been established in pediatric patients weighing at least 14 kg [see Indications and Usage (1.1) and Dosage and Administration (2.2)].

. . .

Use of TYBOST and Atazanavir

Adolescent Patients Weighing at Least 35 kg:

Use of TYBOST and atazanavir is supported by evidence from adequate and well- controlled studies in adults, and by safety, pharmacokinetic, and efficacy data from an open-label trial (Trial 128; cohort 1 [Part A]) in pediatric participants with HIV-1 at least 12 years of age (n=14). The safety, pharmacokinetics, and effectiveness in these participants were similar to that in adults [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)].

Pediatric Patients Weighing at Least 14 kg to Less than 35 kg:

Use of TYBOST and Atazanavir with Tenofovir Alafenamide (TAF)

The use of TYBOST in combination with atazanavir and TAF in pediatric patients weighing less than 35 kg is not recommended.

The use of TYBOST with atazanavir and emtricitabine/tenofovir alafenamide (FTC/TAF) was studied in pediatric participants weighing at least 14 kg to less than 35 kg. In Trial 128, patients who received ATV +cobicistat in cohort 2 (25 kg to <40 kg, n=14) and cohort 3 (14 kg to <25 kg, n=15) showed TAF exposures (Cmax and AUC) that exceeded adult exposures by 4-5-fold in cohort 2 and 2-3- fold in cohort 3. Limited safety data were available to support the increased TAF exposures. Therefore, the use of TYBOST with atazanavir and TAF is not recommended in pediatric participants weighing at least 14 kg to less than 35 kg [see Drug Interactions (7.3)]

Use of TYBOST and Atazanavir with other antiretrovirals other than TAF

Use of TYBOST and atazanavir is supported by evidence from adequate and well-controlled studies in adults, and by pharmacokinetic data from Trial 128 in pediatric participants weighing at least 14 kg to less than 35 kg. In this population, the pharmacokinetics of atazanavir and cobicistat were similar to adults [see Clinical Pharmacology (12.3)].

Pediatric Patients Weighing Less than 14 kg:

Safety, pharmacokinetics, and effectiveness of TYBOST in combination with atazanavir in pediatric participants weighing less than 14 kg have not been established.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

. . .

Lactation

Inform individuals with HIV-1 infection that the potential risks of breastfeeding include: (1) HIV-1 transmission to HIV-1–negative infants, (2) developing viral resistance in HIV- 1–positive infants, and (3) adverse reactions in a breastfed infant similar to those seen in adults [see Use in Specific Populations (8.2)].

. . .

PATIENT INFORMATION

Additions and/or revisions underlined:

. . .

What is TYBOST?

TYBOST is a prescription medicine used in adults and children who weigh at least 31 pounds (14 kg):

1 time each day with the Human Immunodeficiency Virus-1 (HIV-1) medicines atazanavir or darunavir, to increase the amount of those medicines in your blood.
TYBOST is not an HIV-1 medicine and does not treat the HIV-1 virus. You must also take all the HIV-1 medicines prescribed by your healthcare provider even if you take TYBOST and atazanavir or darunavir.
TYBOST should not be used if you take darunavir when prescribed by your healthcare provider to be taken 2 times each day, or if you take other HIV-1 protease inhibitor medicines, including fosamprenavir, saquinavir, or tipranavir.

It is not known if TYBOST when taken with atazanavir is safe and effective in children who weigh less than 31 pounds (14 kg) of if TYBOST when taken with darunavir is safe and effective in children who weigh less than 33 pounds (15 kg).

. . .

Before you take TYBOST, tell your healthcare provider about all of your medical conditions, including if you:

. . .

are pregnant or plan to become pregnant. It is not known if TYBOST can harm your unborn baby.

TYBOST should not be used during pregnancy because you may not have enough TYBOST in your body during pregnancy.
TYBOST may reduce how well some hormonal birth control (contraceptives) works. You should consider using a different form of birth control or an additional barrier method of birth control during treatment with TYBOST.
Tell your healthcare provider if you become pregnant during treatment with TYBOST. Your healthcare provider may prescribe different medicines if you become pregnant during treatment with TYBOST.

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

are breastfeeding or plan to breastfeed. It is not known if TYBOST can pass to your baby in your breast milk. Talk to your healthcare provider about the following risks to your baby from breastfeeding during treatment with TYBOST:

the HIV-1 virus may pass to your baby if your baby does not have HIV-1.
the HIV-1 virus may become harder to treat if your baby has HIV-1.
your baby may get side effects from TYBOST.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, antacids, vitamins, and herbal supplements. TYBOST with atazanavir or darunavir may affect the way other medicines work, and other medicines may affect how TYBOST with atazanavir or darunavir works.

. . .

How should I take TYBOST?

. . .

Stay under the care of your healthcare provider during treatment with TYBOST. See your healthcare provider regularly during treatment with TYBOST.

. . .

What are the possible side effects of TYBOST? TYBOST may cause serious side effects, including:

Kidney problems. TYBOST when taken with certain other medicines can cause new or worse kidney problems, including kidney failure. Your healthcare provider should do blood and urine tests to check your kidneys before you start and during treatment with TYBOST.

The most common side effects of TYBOST with atazanavir include: yellowing of the skin or the whites of your eyes and rash.

. . .

06/20/2025 (SUPPL-18)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

. . .

Adverse Reactions from Clinical Trials Experience in Pediatric Participants

7 Drug Interactions

7.3 Established and Other Potentially Significant Interactions

. . .

Table 7 Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction

Extensive changes to table; please refer to label for complete information.

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Pregnancy Exposure Registry

. . .

Data

Human Data

. . .

8.2 Lactation

Additions and/or revisions underlined:

Risk Summary

There is no information regarding the presence of cobicistat in human milk, the effects on the breastfed infant, or the effects on milk production. Cobicistat is present in rat milk (see Data).

Animal Data

8.4 Pediatric Use

Additions and/or revisions underlined:

Use of TYBOST and Darunavirv

Adolescent Patients Weighing at Least 40 kg

Use of TYBOST and darunavir for this indication is supported by evidence from adequate and well-controlled studies in adults, and by pharmacokinetic, safety, and virologic data from an open-label trial (Trial 128; cohort 1 [Part A]) in virologically suppressed pediatric participants with HIV-1 aged 12 years and older (n=7). The safety, pharmacokinetics, and effectiveness in these participants were similar to that in adults [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)].

Pediatric Patients Weighing at Least 15 kg to Less than 40 kg:

Use of TYBOST and darunavir in combination with other ARVs is supported by evidence from adequate and well-controlled studies in adults, and by pharmacokinetic, safety, and efficacy data from an open-label trial (Trial 128; cohorts 2 and 3) in pediatric participants with HIV-1 at least 2 years of age and weighing at least 15 kg to less than 40 kg (n=20, all of whom were virologically suppressed at baseline).

The safety, pharmacokinetics, and effectiveness of TYBOST when administered with darunavir in pediatric patients weighing at least 15 kg to less than 40 kg were similar to that in adults [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)].

Pediatric Patients Weighing Less than 15 kg:

Safety, pharmacokinetics, and effectiveness of TYBOST in combination with darunavir in pediatric patients weighing less than 15 kg have not been established.

. . .

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

. . .

Lactation

. . .

PATIENT INFORMATION

Additions and/or revisions underlined:

. . .

What is TYBOST?

TYBOST is a prescription medicine used in adults and children who weigh at least 31 pounds (14 kg):

1 time each day with the Human Immunodeficiency Virus-1 (HIV-1) medicines atazanavir or darunavir, to increase the amount of those medicines in your blood.
TYBOST is not an HIV-1 medicine and does not treat the HIV-1 virus. You must also take all the HIV-1 medicines prescribed by your healthcare provider even if you take TYBOST and atazanavir or darunavir.
TYBOST should not be used if you take darunavir when prescribed by your healthcare provider to be taken 2 times each day, or if you take other HIV-1 protease inhibitor medicines, including fosamprenavir, saquinavir, or tipranavir.

. . .

Before you take TYBOST, tell your healthcare provider about all of your medical conditions, including if you:

. . .

are pregnant or plan to become pregnant. It is not known if TYBOST can harm your unborn baby.

TYBOST should not be used during pregnancy because you may not have enough TYBOST in your body during pregnancy.
TYBOST may reduce how well some hormonal birth control (contraceptives) works. You should consider using a different form of birth control or an additional barrier method of birth control during treatment with TYBOST.
Tell your healthcare provider if you become pregnant during treatment with TYBOST. Your healthcare provider may prescribe different medicines if you become pregnant during treatment with TYBOST.

are breastfeeding or plan to breastfeed. It is not known if TYBOST can pass to your baby in your breast milk. Talk to your healthcare provider about the following risks to your baby from breastfeeding during treatment with TYBOST:

the HIV-1 virus may pass to your baby if your baby does not have HIV-1.
the HIV-1 virus may become harder to treat if your baby has HIV-1.
your baby may get side effects from TYBOST.

. . .

How should I take TYBOST?

. . .

Stay under the care of your healthcare provider during treatment with TYBOST. See your healthcare provider regularly during treatment with TYBOST.

. . .

What are the possible side effects of TYBOST? TYBOST may cause serious side effects, including:

Kidney problems. TYBOST when taken with certain other medicines can cause new or worse kidney problems, including kidney failure. Your healthcare provider should do blood and urine tests to check your kidneys before you start and during treatment with TYBOST.

The most common side effects of TYBOST with atazanavir include: yellowing of the skin or the whites of your eyes and rash.

. . .

08/21/2020 (SUPPL-15)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Risk of Serious Adverse Reactions of Loss of Virologic Response Due to Drug Interactions

Additions and/or revisions underlined:

Initiation of TYBOST, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A, or initiation of medications metabolized by CYP3A in patients already receiving TYBOST, may increase plasma concentrations of medications metabolized by CYP3A and reduce plasma concentrations of active metabolite(s) formed by CYP3A. Initiation of medications …

… Decreased concentrations may lead to:

loss of therapeutic effect of the concomitant medications from lower exposures of concomitant drugs or active metabolite(s).

7 Drug Interactions

7.1 Potential Effect of Cobicistat (Coadministered with Atazanavir or Darunavir) on the Pharmacokinetics of Concomitant Drugs

Additions and/or revisions underlined:

Coadministration of TYBOST with atazanavir or darunavir with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Coadministration with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s). Coadministration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 6.

8 Use in Specific Populations

8.1 Pregnancy

Data

Human Data

Additions and/or revisions underlined:

The APR has received prospective reports of live births following exposure to cobicistat- containing regimens during pregnancy, including over 400 exposures in the first trimester and over 80 exposures 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 trimester and second/third trimester exposure, respectively, to cobicistat-containing regimens. 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.

10/03/2019 (SUPPL-14)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions and/or revisions are underlined)

…

Table 3 Selected Adverse Reactions (Grades 2-4) Reported in greater than or equal to 2% of HIV-1 Infected Treatment-Naïve Adults in the TYBOST Coadministered with Atazanavir Group in Trial 114 (Week 144 Analysis)

…

Laboratory Abnormalities: The frequency of laboratory abnormalities (Grades 3-4) occurring in at least 2% of subjects in the TYBOST group in Trial 114 is presented in Table 4.

Table 4 Laboratory Abnormalities (Grades 3-4) in greater than or equal to 2% of HIV-1 Infected Treatment-Naïve Adults in the TYBOST Coadministered with Atazanavir Group in Trial 114 (Week 144 Analysis)

…

Table 5 Lipid Values, Mean Change from Baseline, Reported in HIV-1 Infected Treatment-Naïve Adults Receiving TYBOST Coadministered with Atazanavir + TRUVADA or Ritonavir Coadministered with Atazanavir

+ TRUVADA in Trial 114 (Week 144 Analysis)

…

Adverse Reactions from Clinical Trials Experience in Pediatric Subjects

The safety of TYBOST was evaluated in HIV-1 infected virologically suppressed pediatric subjects between the ages of 12 to less than 18 years through Week 48 in an open-label clinical trial (Trial 128) of TYBOST coadministered with atazanavir (N=14) or darunavir (N=7) plus two nucleoside reverse transcriptase inhibitors. In this trial, the safety profile of TYBOST was similar to that in adults.

7 Drug Interactions

7.1 Potential Effect of Cobicistat (Coadministered with Atazanavir or Darunavir) on the Pharmacokinetics of Concomitant Drugs

(additions and/or revisions are underlined)

…

Coadministration of TYBOST with atazanavir or darunavir with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Coadministration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 6.

7.3 Established and Other Potentially Significant Interactions

(additions and/or revisions are underlined)

…

In Table 6, if not specifically stated, the drug interaction information applies to both coadministered agents: TYBOST coadministered with atazanavir or darunavir.

In addition to the drug interactions noted in Table 6, TYBOST is not recommended for use in combination with fixed-dose combination tablets that contain cobicistat, lopinavir/ritonavir or regimens containing ritonavir, or in combination with more than one antiretroviral agent that requires pharmacokinetic enhancement.

…

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

…

8 Use in Specific Populations

8.4 Pediatric Use

(additions and/or revisions are underlined)

weighing at least 35 kg for TYBOST coadministered with atazanavir or

weighing at least 40 kg for TYBOST coadministered with darunavir.

Use of TYBOST for this indication is supported by evidence from adequate and well- controlled studies in adults, and by pharmacokinetic, safety, and virologic data from an open-label trial (Trial 128) in virologically suppressed, HIV-1 infected pediatric subjects aged 12 years and older. The safety in these subjects through 48 weeks was similar to that in antiretroviral treatment-naïve adults.

Safety and effectiveness of TYBOST in combination with atazanavir in pediatric patients weighing less than 35 kg have not been established. Safety and effectiveness of TYBOST in combination with darunavir in pediatric patients weighing less than 40 kg have not been established.

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

PATIENT INFORMATION

(additions and/or revisions are underlined)

What is TYBOST?

TYBOST is a prescription medicine used in adults and children:

1 time each day with the Human Immunodeficiency Virus-1 (HIV-1) medicines atazanavir or darunavir, to increase the amount of those medicines in your blood.
- When taken with atazanavir, TYBOST is used in adults, and in children who weigh at least 77 pounds (35 kg).
- When taken with darunavir, TYBOST is used in adults, and in children who weigh at least 88 pounds (40 kg).

TYBOST is not an antiretroviral medicine and does not treat the HIV-1 virus. You must also take all the antiretroviral HIV-1 medicines prescribed by your healthcare provider even if you take TYBOST and atazanavir or darunavir.
TYBOST should not be used if you take darunavir when prescribed by your healthcare provider to be taken 2 times each day, or if you take other HIV-1 protease inhibitor medicines, including fosamprenavir, saquinavir, or tipranavir.

It is not known if TYBOST when taken with atazanavir is safe and effective in children who weigh less than 77 pounds (35 kg).

It is not known if TYBOST when taken with darunavir is safe and effective in children who weigh less than 88 pounds (40 kg).

08/22/2019 (SUPPL-13)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

Adverse Reactions from Clinical Trials Experience in Adults

The safety of TYBOST is based on Week 144 data from a Phase 3 trial, Trial 114, in which 692 …

Adverse Reactions from Clinical Trials Experience in Pediatric Subjects

The safety of TYBOST was evaluated in HIV-1 infected virologically suppressed pediatric subjects between the ages of 12 to less than 18 years through Week 48 in an open-label clinical trial (Trial 128) of TYBOST coadministered with atazanavir (N=14) plus two nucleoside reverse transcriptase inhibitors. In this trial, the safety profile of TYBOST was similar to that in adults.

8 Use in Specific Populations

Additions and/or revisions underlined:

8.1 Pregnancy

… In a clinical trial of individuals taking cobicistat coadministered with darunavir, exposures of cobicistat and darunavir were substantially lower during the second and third trimesters of pregnancy.

Data

Human Data

The APR has received prospective reports of live births following exposure to cobicistat- containing regimens during pregnancy, including 258 exposures in the first trimester and 64 exposures in the second/third trimester. Birth defects occurred in 6 of 258 (2.3%, 95% CI: 0.9% to 5.0%) live births …

8.4 Pediatric Use

The safety and effectiveness of TYBOST coadministered with atazanavir and two nucleoside reverse transcriptase inhibitors for the treatment of HIV-1 infection have been established in virologically suppressed pediatric patients weighing at least 35 kg.

10/30/2018 (SUPPL-12)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions are underlined)

...

Lipid-modifying Agents: lomitapide, lovastatin, simvastatin

…

5 Warnings and Precautions

5.2 New Onset or Worsening Renal Impairment When Used with Tenofovir Disoproxil Fumarate

(Additions and/or revisions are underlined)

Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported when TYBOST was used in an antiretroviral regimen that contained TDF.

Coadministration of TYBOST and TDF is not recommended in patients who have an estimated creatinine clearance below 70 mL/min because dose adjustment of TDF is required below 50 mL/min and such dose adjustments have not been established for coadministration with TYBOST .
Document urine glucose and urine protein at baseline and perform routine monitoring of estimated creatinine clearance, urine glucose, and urine protein during treatment when TYBOST is used with TDF. Measure serum phosphorus in patients with or at risk for renal impairment when used with TDF.

...

7 Drug Interactions

7.3 Established and Other Potentially Significant Interactions

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

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions are underlined)

Pregnancy Exposure Registry

Risk Summary

TYBOST coadministered with darunavir or atazanavir is not recommended during pregnancy [see Dosage and Administration (2.4)]. In a clinical trial of individuals taking cobicistat coadministered with darunavir, exposures of cobicistat and darunavir were substantially lower during pregnancy .

TYBOST use during pregnancy has been evaluated in a limited number of individuals as reported by the APR, and available data show no difference in the rate of overall birth defects for cobicistat compared with the background rate for major defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). 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%.

In animal reproduction studies in rats and rabbits, no evidence of fetal harm was observed with oral administration of cobicistat during organogenesis at doses that produced exposures up to 1.4 and 3.3 times, respectively, the maximal recommended human dose (MRHD) of 150 mg (see Data). Because TYBOST is coadministered with atazanavir or darunavir and other antiretroviral drugs, also refer to the prescribing information of each drug for information about pregnancy.

Data

Human Data

Cobicistat coadministered with darunavir as a fixed dose combination, in combination with a background regimen, was evaluated in a clinical trial of 7 pregnant individuals taking darunavir/cobicistat prior to enrollment and who were willing to remain on darunavir/cobicistat 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 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 individuals had sustained virologic response (HIV-1 RNA <50 copies/mL) throughout the study period. There are no clinical data on the virologic response when darunavir/cobicistat is initiated during pregnancy.

There were no new clinically relevant safety findings compared with the known safety profile of darunavir/cobicistat in HIV-1-infected adults.

The APR has received prospective reports of live births following exposure to cobicistat- containing regimens during pregnancy, including 204 exposures in the first trimester and 58 exposures in the second/third trimester. Birth defects occurred in 5 of 204 (2.5%, 95% CI: 0.8% to 5.6%) live births with first trimester exposure of cobicistat-containing regimens. Insufficient numbers of pregnancies with earliest exposure to cobicistat in the second/third trimesters have been reported to the APR to estimate the rate of birth defects in this population. Among pregnant mothers in the U.S. reference population, the background rate of birth defects is 2.7%. There was no association between cobicistat and overall birth defects observed in the APR. Prospective reports from the APR of overall major birth defects in pregnancies exposed to cobicistat 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.

…

8.3 Females and Males of Reproductive Potential

(Newly added subsection)

Contraception

TYBOST interacts with certain oral contraceptives.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

…

New Onset or Worsening Renal Impairment

Inform patients that renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported when TYBOST is used in combination with a TDF containing regimen.

Pregnancy

Advise patients that TYBOST is not recommended during pregnancy and to alert their healthcare provider if they get pregnant while taking TYBOST.

Inform patients that there is a pregnancy exposure registry that monitors fetal outcomes in pregnant individuals exposed to TYBOST during pregnancy.

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)

….

Do not take TYBOST combined with atazanavir or darunavir if you also take any of the following medicines:

alfuzosin hydrochloride (UROXATRAL®)
carbamazepine (CARBATROL®, EPITOL®, EQUETRO®, TEGRETOL®)
cisapride (PROPULSID®, PROPULSID® QUICKSOLV)
colchicine (COLCRYS , MITIGARE™), if you have liver or kidney problems
dronedarone hydrochloride (MULTAQ®)
ergot-containing medicines:
dihydroergotamine mesylate (D.H.E. 45®, MIGRANAL®)
ergotamine tartrate (CAFERGOT®, MIGERGOT®, ERGOSTAT®, MEDIHALER ERGOTAMINE®, WIGRAINE®, WIGRETTES®)
methylergonovine maleate (ERGOTRATE®, METHERGINE®)
lomitapide
…

...

What should I tell my healthcare provider before taking TYBOST? Before you take TYBOST, tell your healthcare provider if you:

have kidney problems
have liver problems
have any other medical conditions
are pregnant or plan to become pregnant
- It is not known if TYBOST can harm your unborn baby.
- TYBOST should not be used during pregnancy because you may not have enough TYBOST in your body during pregnancy.
- Tell your healthcare provider if you become pregnant while taking TYBOST. Your healthcare provider may prescribe different medicines if you become pregnant while taking TYBOST.

…

07/27/2018 (SUPPL-11)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions are underlined)

The concomitant use of TYBOST with atazanavir or darunavir and the following drugs is contraindicated due to the potential for serious and/or life-threatening events or loss of therapeutic effect.

Alpha 1-adrenoreceptor antagonist: alfuzosin
Antianginal: ranolazine
Antiarrhythmic: dronedarone
Anticonvulsants: carbamazepine, phenobarbital, phenytoin
Anti-gout: colchicine
Antimycobacterial: rifampin
Antineoplastics: irinotecan*
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
Hormonal Contraceptives: drospirenone/ ethinyl estradiol*Non-nucleoside Reverse Transcriptase Inhibitor: nevirapine*
Phosphodiesterase-5 (PDE-5) Inhibitor: sildenafil when administered as Revatio® for the treatment of pulmonary arterial hypertension
Protease Inhibitor: indinavir*
Sedative/hypnotics triazolam, orally administered midazolam
*These contraindications apply only to TYBOST coadministered with atazanavir

7 Drug Interactions

7.3 Established and Other Potentially Significant Interactions

(Please refer to Table 5 for Addition of Anticoagulants Drug Interactions)

08/28/2017 (SUPPL-8)

Approved Drug Label (PDF)

4 Contraindications

Table 2 Drugs that are Contraindicated with Concomitant use with TYBOST and Atazanavir or Darunavir

Addition of the following:

Hormonal Contraceptives (drospirenone/ethinyl estradiol) Please see label for complete information.

7 Drug Interactions

Addition of the following:

Hormonal Contraceptives (drospirenone/ethinyl estradiol) Please see label for complete information.

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

PATIENT INFORMATION

Addition of the following:

Do not take TYBOST with atazanavir if you also take any of the following medicines:

drospirenone/ethinyl estradiol (BEYAZ® SAFYRAL®, YASMIN®, YAZ®)

05/05/2017 (SUPPL-7)

Approved Drug Label (PDF)

7 Drug Interactions

7.3 Established and Other Potentially Significant Interactions

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

7.4 Drugs without Clinically Significant Interactions with TYBOST

(new subsection added)

No clinically significant drug interactions have been either observed or are expected when TYBOST is combined with the following drugs: beclomethasone and prednisolone.

06/17/2016 (SUPPL-5)

Approved Drug Label (PDF)

4 Contraindications

Table 2 Drugs that are Contraindicated with Concomitant use with Tybost and Atazanaivr or Darunavir

Three drug classes added; please refer to label:

Antianginal (ranolazine)
Anti-gout (colcichine)
Antipsychotics (lurasidone and pimozide)

5 Warnings and Precautions

Antiretrovirals that are Not Recommended in Combination with TYBOST (addition to subheading)

7 Drug 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

New Drug Class added; please refer to label:

Antipsychotic Drug class (perphenazine, risperidone, thioridazine, and quetiapine)

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

PCI - has been reformatted – refer to label.

PI - Do not take TYBOST combined with atazanavir or darunavir if you also take any of the following medicines:

alfuzosin hydrochloride (UROXATRAL®)
carbamazepine (CARBATROL®, EPITOL®, EQUETRO®, TEGRETOL®)
cisapride (PROPULSID®, PROPULSID® QUICKSOLV)
colchicine (COLCRYS , MITIGARE™), if you have liver or kidney problems
dronedarone hydrochloride (MULTAQ®)
ergot-containing medicines:
- dihydroergotamine mesylate (D.H.E. 45®, MIGRANAL®)
- ergotamine tartrate (CAFERGOT®, MIGERGOT®, ERGOSTAT®, MEDIHALER ERGOTAMINE®, WIGRAINE®, WIGRETTES®)
- methylergonovine maleate (ERGOTRATE®, METHERGINE®)
lovastatin (ADVICOR®, ALTOPREV®, MEVACOR®)
lurasidone (LATUDA®)
midazolam (VERSED®), when taken by mouth
phenobarbital (LUMINAL®)
phenytoin (DILANTIN®, PHENYTEX®)
pimozide (ORAP®)
ranolazine (RANEXA®)
rifampin (RIFADIN®, RIFAMATE®, RIFATER®, RIMACTANE®)
sildenafil (REVATIO®), when used for treating the lung problem pulmonary arterial hypertension (PAH)
simvastatin (SIMCOR®, VYTORIN®, ZOCOR®)
St. John’s wort (Hypericum perforatum) or a product that contains St. John’s wort
triazolam (HALCION®)