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Tybost

Last reviewed on RxList: 10/21/2019
Drug Description

TYBOST®
(cobicistat) Tablets

DESCRIPTION

TYBOST (cobicistat) is a mechanism-based CYP3A inhibitor.

The chemical name for cobicistat is 1,3-thiazol-5-ylmethyl [(2R,5R)-5-{[(2S)-2- [(methyl{[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl}carbamoyl)amino]-4-(morpholin-4- yl)butanoyl]amino}-1,6-diphenylhexan-2-yl]carbamate. It has a molecular formula of C40H53N7O5S2 and a molecular weight of 776.0. It has the following structural formula:

TYBOST® (cobicistat) Structural Formula - Illustration

Cobicistat is adsorbed onto silicon dioxide. Cobicistat on silicon dioxide is a white to pale yellow solid with a solubility of 0.1 mg/mL in water at 20 °C.

TYBOST tablets are for oral administration. Each tablet contains 150 mg of cobicistat. The tablets include the following inactive ingredients: silicon dioxide, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The tablets are film-coated with a coating material containing the following inactive ingredients: polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, sunset yellow FCF (FD&C Yellow #6) aluminum lake, and iron oxide yellow.

Indications

INDICATIONS

Indications

Adult Patients

TYBOST is a CYP3A inhibitor indicated to increase systemic exposure of atazanavir or darunavir (once daily dosing regimen) in combination with other antiretroviral agents in the treatment of HIV-1 infection in adults [see DOSAGE AND ADMINISTRATION].

Pediatric Patients

TYBOST is a CYP3A inhibitor indicated to increase systemic exposure of atazanavir or darunavir (once daily dosing regimen) in combination with other antiretroviral agents in the treatment of HIV-1 infection in pediatric patients [see DOSAGE AND ADMINISTRATION]:

  • weighing at least 35 kg coadministered with atazanavir or
  • weighing at least 40 kg coadministered with darunavir.

Limitations Of Use

  • TYBOST is not interchangeable with ritonavir to increase systemic exposure of darunavir 600 mg twice daily, fosamprenavir, saquinavir, or tipranavir due to lack of exposure data. The use of TYBOST is not recommended with darunavir 600 mg twice daily, fosamprenavir, saquinavir, or tipranavir [see WARNINGS AND PRECAUTIONS].
  • Complex or unknown mechanisms of drug interactions preclude extrapolation of ritonavir drug interactions to certain TYBOST interactions. TYBOST and ritonavir when administered with either atazanavir or darunavir may result in different drug interactions when used with concomitant medications [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY].

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Dosage

DOSAGE AND ADMINISTRATION

Recommended Dosage In Adults

Administer TYBOST in conjunction with atazanavir or darunavir and other antiretroviral agents in the treatment of adults with HIV-1 infection. The recommended dosages of TYBOST and atazanavir or darunavir given with food are presented in Table 1. TYBOST must be coadministered at the same time as atazanavir or darunavir [see DRUG INTERACTIONS]. Consult the prescribing information for atazanavir or darunavir.

Table 1 Recommended Dosing Regimens in Treatment-Naïve orTreatment-Experienced Adults

TYBOST Dosage Coadministered Agent Dosage Patient Populations
150 mg orally once daily atazanavir 300 mg orally once daily Treatment-naïve or treatment-experienced
darunavir 800 mg orally once daily Treatment-naïve or treatment-experienced with no darunavir resistance-associated substitutions

Recommended Dosage In Pediatric Patients

Administer TYBOST in conjunction with atazanavir or darunavir and other antiretroviral agents in the treatment of pediatric patients with HIV-1 infection. The recommended dosages of TYBOST and atazanavir or darunavir given with food are based on weight and presented in Table 2. TYBOST must be coadministered at the same time as atazanavir or darunavir [see DRUG INTERACTIONS]. Consult the prescribing information for atazanavir or darunavir.

Table 2 Recommended Dosing Regimens in Treatment-Naïve orTreatment-Experienced Pediatric Patients

TYBOST Dosage Coadministered Agent Dosage Patient Populations and Weight
150 mg orally once daily atazanavir 300 mg orally once daily Treatment-naïve or treatment-experienced weighing at least 35 kg
darunavir 800 mg orally once daily Treatment-naïve or treatment-experienced with no darunavir resistance-associated substitutions weighing at least 40 kg

Testing Prior To Initiation Of TYBOST

Prior to or when initiating TYBOST and during treatment with TYBOST, on a clinically appropriate schedule, assess estimated creatinine clearance because TYBOST decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function [see WARNINGS AND PRECAUTIONS]. When coadministering TYBOST with TDF, assess estimated creatinine clearance, urine glucose, and urine protein at baseline. In patients with chronic kidney disease, also assess serum phosphorus [see WARNINGS AND PRECAUTIONS].

Renal Impairment

TYBOST coadministered with 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 [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].

Not Recommended During Pregnancy

TYBOST coadministered with darunavir is not recommended for use during pregnancy because of substantially lower exposures of darunavir and cobicistat during the second and third trimesters [see Use In Specific Populations and CLINICAL PHARMACOLOGY].

TYBOST coadministered with atazanavir is not recommended for use during pregnancy because of substantially lower exposures of cobicistat during the second and third trimesters [see Use In Specific Populations and CLINICAL PHARMACOLOGY].

TYBOST coadministered with darunavir or atazanavir should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with TYBOST coadministered with darunavir or atazanavir.

HOW SUPPLIED

Dosage Forms And Strengths

Orange, round, biconvex, film-coated tablets debossed with “GSI” on one side and plain faced on the other side providing 150 mg of cobicistat.

Storage And Handling

TYBOST tablets, 150 mg, are orange, round, biconvex, film-coated, and debossed with “GSI” on one side and plain faced on the other side.

Each bottle contains 30 tablets (NDC 61958-1401-1) and a silica gel desiccant, with a child-resistant closure.

Store at 25 °C (77 °F); excursions permitted to 15–30 °C (59–86 °F) (see USP Controlled Room Temperature).

  • Keep container tightly closed.
  • Dispense only in original container.
  • Do not use if seal over bottle opening is broken or missing.

Manufactured and distributed by: Gilead Sciences, Inc. Revised: Oct 2019

Side Effects

SIDE EFFECTS

The following adverse reaction is described in greater detail in another section of the labeling:

  • New Onset or Worsening Renal Impairment When Used with Tenofovir Disoproxil Fumarate [see WARNINGS AND PRECAUTIONS].

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

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 HIV-1 infected, antiretroviral treatment-naïve subjects received:

  • TYBOST coadministered with atazanavir and TDF/emtricitabine (administered as TRUVADA) (N=344) or
  • ritonavir coadministered with atazanavir and TDF/emtricitabine (administered as TRUVADA) (N=348).

The most common adverse reactions (Grades 2−4) and reported in >5% of subjects in the TYBOST group were jaundice (6%) and rash (5%). The proportion of subjects who discontinued study treatment due to adverse events, regardless of severity, was 11% in both the TYBOST and ritonavir groups. Table 3 displays the frequency of adverse reactions (Grades 2−4) occurring in at least 2% of subjects in the TYBOST group in Trial 114.

Table 3 - Selected Adverse Reactionsa (Grades 2−4) Reported in ≥2% of HIV-1 Infected Treatment-Naïve Adults in the TYBOST Coadministered with Atazanavir Group in Trial 114 (Week 144 Analysis)

  TYBOST Coadministered with Atazanavir + TRUVADA
N=344
Ritonavir Coadministered with Atazanavir + TRUVADA
N=348
Jaundice 6% 3%
Rashb 5% 4%
Ocular icterus 4% 2%
Nausea 2% 2%
Diarrhea 2% 1%
Headache 2% 1%
a. Frequencies of adverse reactions are based on Grades 2−4 adverse events attributed to study drugs.
b. Rash events include dermatitis allergic, drug hypersensitivity, pruritus generalized, eosinophilic pustular folliculitis, rash, rash generalized, rash macular, rash maculo-papular, rash morbilliform, rash papular, and urticaria.

Less Common Adverse Reactions

Selected adverse reactions of at least moderate severity (≥Grade 2) occurring in less than 2% of subjects receiving TYBOST coadministered with atazanavir and TRUVADA are listed below. These events have been included because of the investigator’s assessment of potential causal relationship and were considered serious or have been reported in more than one subject treated with TYBOST and with greater frequency compared with ritonavir.

Gastrointestinal Disorders: vomiting, upper abdominal pain

General Disorders and Administration Site Conditions: fatigue

Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis

Psychiatric Disorders: depression, abnormal dreams, insomnia

Renal and Urinary Disorders: nephropathy, Fanconi syndrome acquired, nephrolithiasis

Refer to the prescribing information for atazanavir or darunavir for information regarding adverse reactions with these drugs.

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 ≥2% of HIV-1 Infected Treatment-Naïve Adults in the TYBOST Coadministered withs Atazanavir Group in Trial 114 (Week 144 Analysis)

  TYBOST + Atazanavir + TRUVADA Ritonavir + Atazanavir + TRUVADA
Laboratory Parameter Abnormality N=344 N=348
Total Bilirubin (>2.5 × ULN) 73% 66%
Creatine Kinase (≥10.0 × ULN) 8% 9%
Urine RBC (Hematuria) (>75 RBC/HPF) 6% 3%
ALT (>5.0 × ULN) 6% 3%
AST (>5.0 × ULN) 4% 3%
GGT (>5.0 × ULN) 4% 2%
Serum Amylasea (>2.0 × ULN) 4% 2%
Urine Glucose (Glycosuria) (≥1000 mg/dL) 3% 3%
Neutrophils (<750/mm3) 3% 2%
Serum Glucose (Hyperglycemia) (>250 mg/dL) 2% 2%
a. For subjects with serum amylase >1.5 × upper limit of normal, lipase test was also performed. The frequency of increased lipase (Grades 3−4) occurring in the TYBOST (N=46) and ritonavir (N=35) groups was 7% and 3%, respectively.

Increase in Serum Creatinine

TYBOST causes increases in serum creatinine and decreases in estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]. In Trial 114, increases in serum creatinine and decreases in estimated creatinine clearance occurred early in treatment with TYBOST, after which they stabilized. The mean (± SD) change in estimated glomerular filtration rate (eGFR) by Cockcroft-Gault method after 144 weeks of treatment was –15.1 ± 16.5 mL/min in the TYBOST group and –8.0 ± 16.8 mL/min in the ritonavir group.

Serum Lipids

Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides are presented in Table 5. In both groups, mean values for serum lipids remained within the study reference range for each laboratory test. The clinical significance of these changes is unknown.

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)

  TYBOST + Atazanavir + TRUVADA Ritonavir + Atazanavir + TRUVADA
Baseline Week 144 Baseline Week 144
mg/dL Change from baselinea mg/dL Change from baselinea
Total Cholesterol (fasted) 163
[N=219]
+11
[N=219]
165
[N=227]
+13
[N=227]
HDL-cholesterol (fasted) 43
[N=218]
+7
[N=218]
43
[N=228]
+6
[N=228]
LDL-cholesterol (fasted) 102
[N=218]
+11
[N=218]
104
[N=228]
+16
[N=228]
Triglycerides (fasted) 130
[N=219]
+14
[N=219]
131
[N=227]
+14
[N=227]
a. The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 144 values. Analysis excludes subjects receiving an HMG-CoA reductase inhibitor drug.

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 [see Clinical Studies]. In this trial, the safety profile of TYBOST was similar to that in adults.

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Drug Interactions

DRUG INTERACTIONS

Potential Effect Of Cobicistat (Coadministered With Atazanavir Or Darunavir) On The Pharmacokinetics Of Concomitant Drugs

Cobicistat is an inhibitor of CYP3A and CYP2D6. The transporters that cobicistat inhibits include p-glycoprotein (P-gp), BCRP, OATP1B1, and OATP1B3. The plasma concentration of drugs that are primarily metabolized by CYP3A or CYP2D6, or are substrates of P-gp, BCRP, OATP1B1, or OATP1B3 may be increased if those drugs are coadministered with TYBOST.

Based on in vitro data, cobicistat is not expected to induce CYP1A2 or CYP2B6 and based on in vivo data, cobicistat is not expected to induce MDR1 or, in general, CYP3A to a clinically significant extent. The induction effect of cobicistat on CYP2C9, CYP2C19, or UGT1A1 is unknown, but is expected to be low based on CYP3A in vitro induction data.

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.

Potential Effect Of Concomitant Drugs On The Pharmacokinetics Of Cobicistat (Coadministered With Atazanavir Or Darunavir)

Cobicistat is metabolized by CYP3A, and to a minor extent, by CYP2D6. Atazanavir and darunavir are also metabolized by CYP3A.

Coadministration of TYBOST with atazanavir or darunavir in combination with drugs that induce CYP3A activity have the potential to decrease plasma concentrations of cobicistat, atazanavir, and darunavir, which may lead to loss of therapeutic effect and development of resistance (see Table 6).

Coadministration of TYBOST with atazanavir or darunavir in combination with other drugs that inhibit CYP3A may further increase the plasma concentrations of cobicistat, atazanavir, and darunavir (see Table 6).

Established And Other Potentially Significant Interactions

Coadministration of TYBOST with fosamprenavir, saquinavir, or tipranavir is not recommended because pharmacokinetic data are not available to provide appropriate dosing recommendations. Use of TYBOST with lopinavir is not recommended because lopinavir is co-formulated with ritonavir.

Table 6 provides dosing recommendations as a result of drug interactions with TYBOST coadministered with atazanavir or darunavir. These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of the interaction and potential for serious adverse events or loss of therapeutic effect [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and CLINICAL PHARMACOLOGY].

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

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 [see WARNINGS AND PRECAUTIONS].

Evaluate whether dosing adjustments of concomitant medications or coadministered antiretroviral drugs are necessary in:

  • Patients on a stable concomitant medication who initiate or switch to a TYBOST-containing regimen
  • Patients on a TYBOST-containing regimen who initiate a new concomitant medication
  • Patients initiating a TYBOST-containing regimen and a new concomitant medication simultaneously

Under these circumstances, also monitor for adverse events and/or monitor concentrations of concomitant medications if appropriate.

No dose adjustment is required when TDF or rilpivirine are coadministered with TYBOST and atazanavir or darunavir.

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

Concomitant Drug Class: Drug Name Potential Effectb Clinical Comment
Antiretroviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
efavirenz ↓ cobicistat
↓ darunavir
↓ atazanavir
TYBOST coadministered with darunavir:
Coadministration of darunavir and TYBOST with efavirenz is not recommended because it may result in the loss of therapeutic effect and development of resistance to darunavir.
TYBOST coadministered with atazanavir:
In treatment-naïve patients: Atazanavir 400 mg with TYBOST 150 mg should be coadministered once daily as a single dose with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime.
In treatment-experienced patients: Coadministration of atazanavir and TYBOST with efavirenz in treatment-experienced patients is not recommended because it may result in the loss of therapeutic effect and development of resistance to atazanavir.
etravirine ↓ cobicistat darunavir: effect unknown
↓ atazanavir
Coadministration with etravirine is not recommended because it may result in the loss of therapeutic effect and development of resistance to atazanavir or darunavir.
nevirapine ↓ atazanavir ↑nevirapine Contraindicated with TYBOST coadministered with atazanavir only:
Coadministration of atazanavir with nevirapine is contraindicated due to potential for loss of atazanavir therapeutic effect and development of resistance, and potential for nevirapine-associated adverse reactions.
↓ cobicistat darunavir: effect unknown TYBOST coadministered with darunavir:
TYBOST coadministration with nevirapine and darunavir is not recommended because it may result in the loss of therapeutic effect and development of resistance to darunavir.
Antiretroviral Agents: CCR5 Antagonists
maraviroc ↑ maraviroc Maraviroc is a substrate of CYP3A. When coadministering with maraviroc, patients should receive maraviroc 150 mg twice daily.
Antiretroviral Agents: Protease Inhibitors
indinavir   Contraindicated with TYBOST coadministered with atazanavir only: Both atazanavir and indinavir are associated with indirect (unconjugated) hyperbilirubinemia.
Other Agents:
Alpha 1 adrenoreceptor antagonist:
alfuzosin
↑alfuzosin Coadministration with alfuzosin is contraindicated due to potential for serious and/or life-threatening reactions such as hypotension.
Antianginal ranolazine ↑ ranolazine Coadministration with ranolazine is contraindicated due to potential for serious and/or life-threatening reactions.
Antacids:
e.g., aluminum and magnesium hydroxide (please also see H2Receptor Antagonists and Proton Pump Inhibitors below)
↓ atazanavir TYBOST coadministered with atazanavir:
With concomitant use, administer a minimum of 2 hours apart.
Antiarrhythmics:
dronedarone
↑ dronedarone Coadministration with dronedarone is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
digoxin ↑ digoxin When coadministering with digoxin, titrate the digoxin dose and monitor digoxin concentrations.
Other antiarrhythmics: e.g.,
amiodarone
disopyramide
flecainide
mexiletine
propafenone
quinidine
↑ antiarrhythmics Clinical monitoring is recommended upon coadministration with antiarrhythmics.
Antibacterials (macrolide or ketolide antibiotics): clarithromycin
erythromycin
telithromycin
↑ clarithromycin
↑ erythromycin
↑ telithromycin
↑ cobicistat
↑ atazanavir
↑ darunavir
Consider alternative antibiotics with concomitant use of TYBOST coadministered with atazanavir or darunavir.
Anticancer Agents:
irinotecan
↑ irinotecan Contraindicated with TYBOST coadministered with atazanavir only: Coadministration of atazanavir with irinotecan is contraindicated due to potential for increased irinotecan toxicity.
dasatinib
nilotinib
vinblastine
vincristine
↑ anticancer agents A decrease in the dosage or an adjustment of the dosing interval of dasatinib or nilotinib may be necessary upon coadministration with TYBOST coadministered with atazanavir or darunavir. Consult the dasatinib and nilotinib prescribing information for
dosing instructions.
For vincristine and vinblastine, monitor for hematologic or gastrointestinal side effects.
Anticoagulants:
Direct Oral Anticoagulants (DOACs) apixaban
rivaroxaban
betrixaban
dabigatran
edoxaban
↑ apixaban TYBOST coadministered with atazanavir or darunavir:
Due to potentially increased bleeding risk, dosing recommendations for coadministration of apixaban with TYBOST depends on the apixaban dose. Refer to apixaban dosing instructions for coadministration with strong CYP3A and P-gp inhibitors in apixaban prescribing information.
↑ rivaroxaban Coadministration of rivaroxaban with TYBOST is not recommended because it may lead to an increased bleeding risk.
atazanavir:
↑ betrixaban
↑ dabigatran
↑ edoxaban
TYBOST coadministered with atazanavir:
Due to potentially increased bleeding risk, dosing recommendations for coadministration of betrixaban, dabigatran, or edoxaban with a P-gp inhibitor such as TYBOST coadministered with atazanavir depends on DOAC indication and renal function. Refer to DOAC dosing instructions for coadministration with P-gp inhibitors in DOAC prescribing information.
darunavir:
↔ betrixaban
↔ dabigatran
↔ edoxaban
TYBOST coadministered with darunavir:
No dose adjustment.
warfarin warfarin: effect unknown Monitor the international normalized ratio (INR) upon coadministration of TYBOST with warfarin.
Anticonvulsants:
carbamazepine, phenobarbital, phenytoin
↓ atazanavir
↓ darunavir
↓ cobicistat
Coadministration with carbamazepine, phenobarbital, or phenytoin is contraindicated due to potential for loss of therapeutic effect and development of resistance.
Anticonvulsants with CYP3A induction effects that are NOT contraindicated
e.g.,
eslicarbazepine,
oxcarbazepine
Anticonvulsants that are metabolized by CYP3A
e.g., clonazepam
↓ cobicistat
↓ atazanavir darunavir: effect unknown
Consider alternative anticonvulsant or antiretroviral therapy to avoid potential changes in exposures. If coadministration is necessary, monitor for lack or loss of virologic response.
↑ clonazepam Clinical monitoring of anticonvulsants is recommended.
Antidepressants:
Selective Serotonin Reuptake Inhibitors (SSRIs)
e.g.,
paroxetine
SSRIs: effects unknown
↑ TCAs
↑ trazodone
When coadministering with SSRIs, TCAs, or trazodone, careful dose titration of the antidepressant to the desired effect, including using the lowest feasible initial or maintenance dose, and monitoring for antidepressant response are recommended.
Tricyclic Antidepressants (TCAs) e.g.,
amitriptyline
desipramine
imipramine
nortriptyline
Other antidepressants: trazodone
Antifungals:
itraconazole
ketoconazole
voriconazole
↑ itraconazole
↑ ketoconazole
Specific dosing recommendations are not available for coadministration with itraconazole or ketoconazole.
Voriconazole:
effects unknown
↑ cobicistat
↑ atazanavir
↑ darunavir
Coadministration with voriconazole is not recommended unless the benefit/risk assessment justifies the use of voriconazole.
Anti-gout:
colchicine
↑ colchicine Coadministration with colchicine is contraindicated in patients with renal and/or hepatic impairment due to potential for serious and/or life-threatening reactions.
Treatment of gout flares – coadministration of colchicine:
0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days.
Prophylaxis of gout flares – coadministration of colchicine:
If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.
Treatment of familial Mediterranean fever – coadministration of colchicine:
Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial:
rifampin
↓ atazanavir
↓ darunavir
↓ cobicistat
Coadministration with rifampin is contraindicated due to potential for loss of therapeutic effect and development of resistance.
rifabutin ↑ rifabutin cobicistat: effects unknown darunavir: effects
unknown
atazanavir: effects
unknown
The recommended dosage regimen for rifabutin is 150 mg every other day. Monitor for rifabutin associated adverse reactions including neutropenia and uveitis.
Antipsychotics:
lurasidone
↑ lurasidone Coadministration with lurasidone is contraindicated due to potential for serious and/or life-threatening reactions.
pimozide ↑ pimozide Coadministration with pimozide is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
quetiapine ↑ quetiapine Initiation of TYBOST coadministered with atazanavir or darunavir 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 TYBOST coadministered with atazanavir or darunavir:
Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
Other antipsychotics:
e.g.,
perphenazine
risperidone
thioridazine
↑ antipsychotic A decrease in the dose of antipsychotics that are metabolized by CYP3A or CYP2D6 may be needed upon coadministration.
Beta-Blockers:
e.g.,
metoprolol
carvedilol
timolol
↑ beta-blockers Clinical monitoring is recommended for coadministration with beta-blockers that are metabolized by CYP2D6.
Calcium Channel Blockers:
e.g., amlodipine
diltiazem
felodipine
nifedipine
verapamil
↑ calcium channel blockers Clinical monitoring is recommended for coadministration with calcium channel blockers metabolized by CYP3A.
Corticosteroids (all routes, excludingcutaneous):
e.g., betamethasone
budesonide
ciclesonide
dexamethasone
fluticasone
methylprednisolone
mometasone
triamcinolone
↓ cobicistat
↓ atazanavir
↓ darunavir
↑ corticosteroids
Coadministration with oral dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to atazanavir or darunavir. Consider alternative corticosteroids. Coadministration with corticosteroids whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression.
Alternative corticosteroids including beclomethasone, prednisone, and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use.
Endothelin ReceptorAntagonists:
bosentan
↑ bosentan
↓ cobicistat
↓ darunavir
↓ atazanavir
Initiation of bosentan in patients taking TYBOST coadministered with atazanavir or darunavir:
In patients who have been receiving TYBOST coadministered with atazanavir or darunavir for at least 10 days, start bosentan at 62.5 mg once daily or every
other day based upon individual tolerability.
Initiation of TYBOST coadministered with atazanavir or darunavir in patients taking bosentan:
Discontinue use of bosentan at least 36 hours prior to initiation of TYBOST coadministered with atazanavir or darunavir. After at least 10 days following the initiation of TYBOST combined with atazanavir or darunavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Switching from ritonavir to TYBOST coadministered with atazanavir or darunavir:
Maintain bosentan dose.
Ergot Derivatives:
dihydroergotamine, ergotamine, methylergonovine
↑ ergot derivatives Coadministration is contraindicated due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI motility agent:
cisapride
↑ cisapride Coadministration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
H2-Receptor Antagonists:
e.g., famotidine
↓ atazanavir TYBOST coadministered with atazanavir:
Administer atazanavir/TYBOST either at the same time or a minimum of 10 hours after administering H2 receptor antagonists. The dose of the H2-receptor antagonist should not exceed a dose comparable to famotidine 40 mg twice daily in treatment-naïve patients or 20 mg twice daily in treatment-experienced patients.
TYBOST coadministered with atazanavir and TDF:
Treatment-experienced patients: The recommended once daily dosage regimen is TYBOST 150 mg coadministered with atazanavir 400 mg with concomitant use of H2-receptor antagonists and tenofovir.
HCV Protease Inhibitors:
boceprevir
simeprevir
darunavir: effects unknown atazanavir: effects unknown boceprevir: effects unknown ↑ simeprevir No drug interaction data are available. Coadministration with boceprevir or simeprevir is not recommended.
Herbal Products:
St. John’s wort (Hypericum perforatum)
↓ atazanavir
↓ darunavir
↓ cobicistat
Coadministration is contraindicated due to potential for loss of therapeutic effect and development of resistance.
Hormonal Contraceptives:   Additional or alternative non-hormonal forms of contraception should be considered when estrogen based contraceptives are coadministered with TYBOST and atazanavir or darunavir.
drospirenone/ethinyl estradiol atazanavir: ↑ drospirenone Contraindicated with TYBOST coadministered with atazanavir only:
Coadministration of atazanavir with drospirenone is contraindicated due to potential for drospirenone-associated hyperkalemia.
  darunavir:
↑ drospirenone
↓ ethinyl estradiol
TYBOST coadministered with darunavir:
For coadministration with drospirenone, clinical monitoring is recommended due to the potential for hyperkalemia.
Other progestin/estrogen contraceptives progestin: effects unknown estrogen: effects unknown No data are available to make recommendations on the coadministration of TYBOST and atazanavir or darunavir with other hormonal contraceptives.
Immuno suppressants:
cyclosporine
everolimus
sirolimus
tacrolimus
↑ immuno-suppressants These immunosuppressant agents are metabolized by CYP3A. Therapeutic drug monitoring is recommended if coadministered.
Inhaled Beta Agonist:
salmeterol
↑ salmeterol Coadministration with salmeterol is not recommended and may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Lipid-modifying Agents: ↑ lovastatin ↑ simvastatin Coadministration with lovastatin or simvastatin is contraindicated due to potential for serious reactions such as myopathy including rhabdomyolysis.
HMG-CoA reductase inhibitors:
lovastatin
simvastatin
   
Other HMG-CoA reductase inhibitors: e.g., atorvastatin
rosuvastatin
↑ HMG-CoA reductase inhibitors Coadministration of atazanavir and TYBOST with atorvastatin is not recommended.
    For HMG-CoA reductase inhibitors that are not contraindicated with TYBOST coadministered with atazanavir or darunavir, start with the lowest recommended dose and titrate while monitoring for safety (e.g., myopathy). Dosage recommendations with atorvastatin or rosuvastatin are as follows.
TYBOST coadministered with atazanavir:
  • Rosuvastatin dosage should not exceed 10 mg
TYBOST coadministered with darunavir:
  • Atorvastatin dosage should not exceed 20 mg
  • Rosuvastatin dosage should not exceed 20 mg
Other lipid-modifying agents: lomitapide ↑ lomitapide Coadministration with lomitapide is contraindicated due to potential for markedly increased transaminases.
Narcotic Analgesics For treatment of opioid dependence:
buprenorphine buprenorphine/ naloxone methadone
buprenorphine or buprenorphine/ naloxone: effects unknown Initiation of buprenorphine, buprenorphine/naloxone, or methadone in patients taking TYBOST coadministered with atazanavir or darunavir:
  methadone: effects unknown Carefully titrate the dose of buprenorphine, buprenorphine/naloxone, or methadone to the desired effect; use the lowest feasible initial or maintenance dose.
Initiation of TYBOST coadministered with atazanavir or darunavir in patients taking buprenorphine, buprenorphine/naloxone, or methadone:
A dose adjustment for buprenorphine, buprenorphine/naloxone, or methadone may be needed. Monitor clinical signs and symptoms.
fentanyl ↑ fentanyl Careful monitoring of therapeutic and adverse effects of fentanyl (including potentially fatal respiratory depression) is recommended with coadministration.
tramadol ↑ tramadol A dose decrease may be needed for tramadol with concomitant use.
Phosphodiesterase 5 (PDE-5) Inhibitors:
avanafil
sildenafil
tadalafil
vardenafil
↑PDE-5 inhibitors Coadministration with avanafil is not recommended because a safe and effective avanafil dosage regimen has not been established.
    Coadministration with TYBOST coadministered with atazanavir or darunavir may result in an increase in PDE-5 inhibitor associated adverse events, including hypotension, syncope, visual disturbances, and priapism.
Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH):
  • Use of sildenafil is contraindicated when used for the treatment of PAH due to potential for sildenafilassociated adverse reactions (which include visual disturbances, hypotension, priapism, and syncope).
  • The following dose adjustments are recommended for tadalafil concomitant use:
Initiation of tadalafil in patients taking TYBOST coadministered with atazanavir or darunavir:
In patients taking TYBOST coadministered with atazanavir or darunavir for at least 1 week, start tadalafil at 20 mg once daily. Increase tadalafil dose to 40 mg once daily based upon individual tolerability.
Initiation of TYBOST coadministered with atazanavir or darunavir in patients taking tadalafil:
Avoid use of tadalafil during the initiation of TYBOST coadministered with atazanavir or darunavir.
Stop tadalafil at least 24 hours prior to starting TYBOST coadministered with atazanavir or darunavir. After at least one week following initiation of TYBOST coadministered with atazanavir or darunavir, resume tadalafil at 20 mg once daily. Increase tadalafil dose to 40 mg once daily based upon individual tolerability.
Patients switching from ritonavir to TYBOST coadministered with atazanavir or darunavir:
Maintain tadalafil dose.
Use of PDE-5 inhibitors for erectile dysfunction:
Sildenafil at a single dose not exceeding 25 mg in 48 hours, tadalafil at a single dose not exceeding 10 mg in 72 hours, or vardenafil at a single dose not exceeding 2.5 mg in 72 hours can be used with increased monitoring for PDE-5 inhibitor associated adverse events.
Proton-pump Inhibitors (PPIs)
e.g., omeprazole
↓ atazanavir TYBOST coadministered with atazanavir:
In treatment-naïve patients, administer TYBOST with atazanavir a minimum of 12 hours after administering PPIs. The dose of the PPI should not exceed a dose comparable to omeprazole 20 mg daily.
In treatment-experienced patients, coadministration with PPIs, with or without tenofovir, is not recommended.
Sedative/Hypnotics:
midazolam (oral), triazolam
↑ midazolam
↑ triazolam
Coadministration with triazolam or oral administered midazolam is contraindicated due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.
Triazolam and orally administered midazolam are extensively metabolized by CYP3A. Coadministration of triazolam or orally administered midazolam with TYBOST may cause large increases in the concentrations of these benzodiazepines.
Other benzodiazepines: e.g., parenterally administered
midazolam
clorazepate
diazepam
estazolam
flurazepam
↑ sedatives/hypnotics Coadministration with parenteral midazolam may increase plasma concentrations of midazolam. Coadministration should be done in a setting that ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosing reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.
buspirone
zolpidem
With other sedatives/hypnotics that are CYP3A metabolized, dose reduction may be necessary and clinical monitoring is recommended.
a. This table is not all inclusive.
b. ↑ = Increase, ↓ = Decrease, ↔ = No change

Warnings & Precautions

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., anaphylaxis, angioedema, urticaria, rash) have occurred following administration of FASENRA. These reactions generally occur within hours of administration, but in some instances have a delayed onset (i.e., days). In the event of a hypersensitivity reaction, FASENRA should be discontinued [see CONTRAINDICATIONS].

Acute Asthma Symptoms Or Deteriorating Disease

FASENRA should not be used to treat acute asthma symptoms or acute exacerbations. Do not use FASENRA to treat acute bronchospasm or status asthmaticus. Patients should seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment with FASENRA.

Reduction Of Corticosteroid Dosage

Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of therapy with FASENRA. Reductions in corticosteroid dose, if appropriate, should be gradual and performed under the direct supervision of a physician. Reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy.

Parasitic (Helminth) Infection

Eosinophils may be involved in the immunological response to some helminth infections. Patients with known helminth infections were excluded from participation in clinical trials. It is unknown if FASENRA will influence a patient’s response against helminth infections.

Treat patients with pre-existing helminth infections before initiating therapy with FASENRA. If patients become infected while receiving treatment with FASENRA and do not respond to anti-helminth treatment, discontinue treatment with FASENRA until infection resolves.

Patient Counseling Information

Advise the patients and/or caregivers to read the FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use for FASENRA PEN) before the patient starts using FASENRA and each time the prescription is renewed as there may be new information they need to know.

Provide proper training to patients and/or caregivers on proper subcutaneous injection technique using the FASENRA PEN, including aseptic technique, and the preparation and administration of FASENRA PEN prior to use. Advise patients to follow sharps disposal recommendations [see Instructions for Use].

Hypersensitivity Reactions

Inform patients that hypersensitivity reactions (e.g., anaphylaxis, angioedema, urticaria, rash) have occurred after administration of FASENRA. These reactions generally occurred within hours of FASENRA administration, but in some instances had a delayed onset (i.e., days). Instruct patients to contact their healthcare provider if they experience symptoms of an allergic reaction [see WARNINGS AND PRECAUTIONS].

Not For Acute Symptoms Or Deteriorating Disease

Inform patients that FASENRA does not treat acute asthma symptoms or acute exacerbations. Inform patients to seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment with FASENRA [see WARNINGS AND PRECAUTIONS].

Reduction Of Corticosteroid Dosage

Inform patients to not discontinue systemic or inhaled corticosteroids except under the direct supervision of a physician. Inform patients that reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy [see WARNINGS AND PRECAUTIONS].

Pregnancy Exposure Registry

Inform women there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to FASENRA during pregnancy and that they can enroll in the Pregnancy Exposure Registry by calling 1-877-311-8972 or by visiting mothertobaby.org/Fasenra [see Use In Specific Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of benralizumab. Published literature using animal models suggests that IL-5 and eosinophils are part of an early inflammatory reaction at the site of tumorigenesis and can promote tumor rejection. However, other reports indicate that eosinophil infiltration into tumors can promote tumor growth. Therefore, the malignancy risk in humans from an antibody that binds to IL-5Rα such as benralizumab is unknown.

Male and female fertility were unaffected based upon no adverse histopathological findings in the reproductive organs from cynomolgus monkeys treated with benralizumab for 9 months at IV doses up to 25 mg/kg or at SC doses of up to 30 mg/kg once every 2 weeks (approximately 400 and 270 times the MRHD on an AUC basis).

Use In Specific Populations

Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to FASENRA during pregnancy. Healthcare providers can enroll patients or encourage patients to enroll themselves by calling 1-877-311-8972 or visiting mothertobaby.org/Fasenra.

Risk Summary

The data on pregnancy exposure from the clinical trials are insufficient to inform on drug-associated risk. Monoclonal antibodies such as benralizumab are transported across the placenta during the third trimester of pregnancy; therefore, potential effects on a fetus are likely to be greater during the third trimester of pregnancy. In a prenatal and postnatal development study conducted in cynomolgus monkeys, there was no evidence of fetal harm with IV administration of benralizumab throughout pregnancy at doses that produced exposures up to approximately 310 times the exposure at the maximum recommended human dose (MRHD) of 30 mg SC [see Data].

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-associated Maternal and/or Embryo/fetal Risk:

In women with poorly or moderately controlled asthma, evidence demonstrates that there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. The level of asthma control should be closely monitored in pregnant women and treatment adjusted as necessary to maintain optimal control.

Data

Animal Data

In a prenatal and postnatal development study, pregnant cynomolgus monkeys received benralizumab from beginning on GD20 to GD22 (dependent on pregnancy determination), on GD35, once every 14 days thereafter throughout the gestation period and 1-month postpartum (maximum 14 doses) at doses that produced exposures up to approximately 310 times that achieved with the MRHD (on an AUC basis with maternal IV doses up to 30 mg/kg once every 2 weeks). Benralizumab did not elicit adverse effects on fetal or neonatal growth (including immune function) up to 6.5 months after birth. There was no evidence of treatment-related external, visceral, or skeletal malformations. Benralizumab was not teratogenic in cynomolgus monkeys. Benralizumab crossed the placenta in cynomolgus monkeys. Benralizumab concentrations were approximately equal in mothers and infants on postpartum day 7, but were lower in infants at later time points. Eosinophil counts were suppressed in infant monkeys with gradual recovery by 6 months postpartum; however, recovery of eosinophil counts was not observed for one infant monkey during this period.

Lactation

Risk Summary

There is no information regarding the presence of benralizumab in human or animal milk, and the effects of benralizumab on the breast fed infant and on milk production are not known. However, benralizumab is a humanized monoclonal antibody (IgG1/κ-class), and immunoglobulin G (IgG) is present in human milk in small amounts. If benralizumab is transferred into human milk, the effects of local exposure in the gastrointestinal tract and potential limited systemic exposure in the infant to benralizumab are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for benralizumab and any potential adverse effects on the breast-fed child from benralizumab or from the underlying maternal condition.

Pediatric Use

There were 108 adolescents aged 12 to 17 with asthma enrolled in the Phase 3 exacerbation trials (Trial 1: n=53, Trial 2: n=55). Of these, 46 received placebo, 40 received FASENRA every 4 weeks for 3 doses, followed by every 8 weeks thereafter, and 22 received FASENRA every 4 weeks. Patients were required to have a history of 2 or more asthma exacerbations requiring oral or systemic corticosteroid treatment in the past 12 months and reduced lung function at baseline (pre-bronchodilator FEV1<90%) despite regular treatment with medium or high dose ICS and LABA with or without OCS or other controller therapy. The pharmacokinetics of benralizumab in adolescents 12 to 17 years of age were consistent with adults based on population pharmacokinetic analysis and the reduction in blood eosinophil counts was similar to that observed in adults following the same FASENRA treatment. The adverse event profile in adolescents was generally similar to the overall population in the Phase 3 studies [see ADVERSE REACTIONS]. The safety and efficacy in patients younger than 12 years of age has not been established.

Geriatric Use

Of the total number of patients in clinical trials of benralizumab, 13% (n=320) were 65 and over, while 0.4% (n=9) were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Overdosage & Contraindications

OVERDOSE

If overdose occurs, the patient must be monitored for evidence of toxicity. Treatment of overdose with TYBOST consists of general supportive measures including monitoring of vital signs, as well as observation of the clinical status of the patient.

As cobicistat is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.

CONTRAINDICATIONS

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 [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].

  • 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)
  • Hormonal Contraceptives: drospirenone/ ethinyl estradiol*
  • Lipid-modifying Agents: lomitapide, lovastatin, simvastatin
  • 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

Clinical Pharmacology

CLINICAL PHARMACOLOGY

Mechanism Of Action

Cobicistat is a mechanism-based inhibitor of cytochrome P450 3A (CYP3A). Inhibition of CYP3A-mediated metabolism by cobicistat increases the systemic exposure of CYP3A substrates atazanavir and darunavir.

Pharmacodynamics

Effects On Pharmacokinetic Enhancement

The effect of TYBOST on atazanavir pharmacokinetics was evaluated in the pharmacokinetic substudy (N=48) of Trial 114 in which HIV-1 infected subjects received atazanavir 300 mg coadministered with TYBOST 150 mg or atazanavir 300 mg coadministered with ritonavir 100 mg, both in combination with TRUVADA. The steady state pharmacokinetic parameters of atazanavir were comparable when coadministered with TYBOST versus ritonavir groups as shown in Table 7 [see Clinical Studies].

Table 7 Pharmacokinetic Parameters (Mean ± SD) of Atazanavir in HIV-1 Infected Treatment-Naïve Adults (Pharmacokinetic Substudy of Trial 114)

Atazanavir Pharmacokinetic Parameters TYBOST + Atazanavir + TRUVADA Once Daily Ritonavir + Atazanavir + TRUVADA Once Daily
N=22 N=26
AUCtau (mcg•hr/mL) 46.13 ± 26.18 47.59 ± 24.38
Cmax (mcg/mL) 3.91 ± 1.94 4.76 ± 1.94
Ctau (mcg/mL) 0.80 ± 0.72 0.85 ± 0.72

The effect of TYBOST on darunavir was evaluated in a clinical study (Trial 115) in 31 healthy subjects who received darunavir 800 mg in combination with TYBOST 150 mg or ritonavir 100 mg, all once daily, for 10 days. With the exception of Ctau, the steady-state pharmacokinetic parameters of darunavir were comparable when coadministered with TYBOST versus ritonavir as shown in Table 8, and these results were similar to those reported in previous clinical trials of darunavir 800 mg with ritonavir 100 mg once daily (refer to prescribing information for darunavir).

Table 8 Pharmacokinetic Parameters (Mean ± SD) of Darunavir in HealthyAdults (Trial 115)

Darunavir Pharmacokinetic Parameters TYBOST + Darunavir Once Daily Ritonavir + Darunavir Once Daily
N=31 N=31
AUCtau (mcg•hr/mL) 81.08 ± 25.15 79.99 ± 27.20
Cmax (mcg/mL) 7.74 ± 1.69 7.46 ± 1.52
C0h (mcg/mL) 2.40 ± 1.22 2.48 ± 0.85
Ctau (mcg/mL) 1.33 ± 0.89 1.87 ± 1.56

Cardiac Electrophysiology

In a thorough QT/QTc study in 48 healthy subjects, a single dose of cobicistat 250 mg and 400 mg (1.67 and 2.67 times the dose in TYBOST) did not affect the QT/QTc interval. Prolongation of the PR interval was noted in subjects receiving cobicistat. The maximum mean (95% upper confidence bound) difference in PR from placebo after baseline-correction was 9.5 (12.1) msec for the 250 mg cobicistat dose and 20.2 (22.8) for the 400 mg cobicistat dose.

Effects On Serum Creatinine

The effect of TYBOST on serum creatinine was investigated in a trial in subjects with normal renal function (eGFR ≥80 mL/min, N=12) and mild-to-moderate renal impairment (eGFR 50–79 mL/min, N=18). A statistically significant decrease in the estimated glomerular filtration rate, calculated by Cockcroft-Gault method (eGFRCG) from baseline, was observed after 7 days of treatment with cobicistat 150 mg among subjects with normal renal function (−9.9 ± 13.1 mL/min) and mild-to-moderate renal impairment (−11.9 ± 7.0 mL/min). No statistically significant changes in eGFRCG were observed compared to baseline for subjects with normal renal function or mild-to-moderate renal impairment 7 days after cobicistat was discontinued. The actual glomerular filtration rate, as determined by the clearance of probe drug iohexol, was not altered from baseline following treatment with TYBOST among subjects with normal renal function and mild-to-moderate renal impairment, indicating that cobicistat inhibits tubular secretion of creatinine, reflected as a reduction in eGFRCG, without affecting the actual glomerular filtration rate [see WARNINGS AND PRECAUTIONS].

Pharmacokinetics

Absorption

In a trial where subjects were instructed to take coadministered TYBOST and darunavir with food, median cobicistat peak plasma concentrations were observed approximately 3.5 hours postdose. Steady-state cobicistat Cmax, AUCtau, and Ctau (mean ± SD) values were 0.99 ± 0.3 mcg/mL (n=60), 7.6 ± 3.7 mcg*hr/mL (n=59), and 0.03 ± 0.1 mcg/mL (n=59), respectively.

Effect Of Food On Oral Absorption

A food-effect trial was not conducted for TYBOST. In clinical trials, TYBOST was coadministered with other antiretroviral agents [see Clinical Studies] under fed conditions, in accordance with the prescribing information for these agents. It is recommended that TYBOST coadministered with atazanavir or darunavir be administered with food [see DOSAGE AND ADMINISTRATION].

Distribution

Cobicistat is 97–98% bound to human plasma proteins and the mean blood-to-plasma ratio was approximately 0.5.

Metabolism

Cobicistat is metabolized by CYP3A and to a minor extent by CYP2D6 enzymes and does not undergo glucuronidation.

Elimination

The terminal plasma half-life of cobicistat following administration of TYBOST is approximately 3 to 4 hours. With single dose administration of [14C] cobicistat after multiple dosing of cobicistat for 6 days, the mean percent of the administered dose excreted in feces and urine was 86.2% and 8.2%, respectively.

Specific Populations

Race And Gender

No clinically relevant differences in the pharmacokinetics of cobicistat were observed based on race or gender.

Pediatric Patients

In pediatric subjects aged 12 to less than 18 years who received TYBOST 150 mg coadministered with atazanavir 300 mg (N=12), geometric mean atazanavir Cmax and AUCtau and cobicistat AUCtau values were approximately 20-30% higher than in adults and geometric mean atazanavir and cobicistat Ctau values were approximately 60% to 160% higher than in adults; the increases were not considered clinically significant. In pediatric subjects aged 12 to less than 18 years who received TYBOST 150 mg coadministered with darunavir 800 mg (N=7), geometric mean darunavir Cmax and AUCtau values were similar between adults and adolescents. Geometric mean darunavir AUCtau and Ctau values were 15% and 32% lower, with geometric mean ratios of 0.85 (90% CI: 0.64, 1.13) and 0.68 (90% CI: 0.30, 1.55) in adolescent subjects relative to adults, respectively. This difference was not considered clinically significant based on exposure-response relationships. Geometric mean cobicistat AUCtau, Cmax, and Ctau values were comparable in adolescents and adults (Table 9).

Table 9 Multiple-Dose PK Parameters of Cobicistat, Atazanavir, and Darunavir Following Administration of TYBOST with Atazanavir or Darunavir in HIV-1 Infected Pediatric Subjects Weighing at Least 35 kga

Parameter Geometric Mean (CV%) Cobicistat Atazanavir Darunavir
Treatment Administered TYBOST + Atazanavir TYBOST + Darunavir TYBOST + Atazanavir TYBOST + Darunavir
Pediatric Subjectsa N=12 N=7 N=12 N=7
  AUCtau (mcg•hr/mL) 12.11 (44.7) 8.33 (34.9) 49.48 (49.1) 77.22 (29.5)
  Cmax (mcg/mL) 1.28 (31.7) 1.10 (20.0) 4.32 (49.9) 7.32 (21.7)
  Ctau (mcg/mL) 0.09 (156.2) 0.02 (123.9)b 0.91 (96.4) 0.68 (91.6)
Adultsc,d N=30c N=21d N=30c N=21d
  AUCtau (mcg•hr/mL) 9.65 (41.8) 7.69 (43.9) 39.96 (52.1) 90.56 (45.3)
  Cmax (mcg/mL) 1.28 (35.6) 1.04 (35.3) 3.54 (45.8) 8.34 (33.3)
  Ctau (mcg/mL) 0.04 (112.7) 0.02 (135.1)e 0.58 (84.7) 1.00 (108.0)
CV=Coefficient of Variation
a. From Intensive PK analysis of Trial 128.
b. N=5; Data from two subjects who had undetectable TYBOST Ctau concentrations were excluded from summary statistics.
c. From pooled Intensive PK analysis of trials with TYBOST + atazanavir.
d. From Intensive PK analysis of Trial GS-US-299-0102 with TYBOST + darunavir.
e. N=18.

Patients With Renal Impairment

No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with severe renal impairment (estimated creatinine clearance below 30 mL/min) and healthy subjects [see Use In Specific Populations].

Patients With Hepatic Impairment

No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with moderate hepatic impairment (Child-Pugh Class B) and healthy subjects. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of cobicistat has not been studied [see Use In Specific Populations].

Pregnancy And Postpartum

The exposure to total and unbound darunavir boosted with cobicistat after intake of darunavir/cobicistat as part of an antiretroviral regimen was substantially lower during the second and third trimesters of pregnancy compared with 6–12 weeks postpartum (see Table 10 and Figure 1).

Table 10: Pharmacokinetic Results of Total Darunavir after Administration of Darunavir/Cobicistat Once Daily as Part of an Antiretroviral Regimen, During the 2nd Trimester of Pregnancy, the 3rd Trimester of Pregnancy, and Postpartum

Pharmacokinetics of total darunavir (mean ± SD) 2nd Trimester of pregnancy
N=7
3rd Trimester of pregnancy
N=6
Postpartum(6−12 weeks)
N=6
Cmax, ng/mL 4,340 ± 1,616 4,910 ± 970 7,918 ± 2,199
AUC24h, ng.h/mL 47,293 ± 19,058 47,991 ± 9,879 99,613 ± 34,862
Cmin, ng/mL 168 ± 149 184 ± 99 1,538 ± 1,344

Figure 1: Pharmacokinetic Results (Within-Subject Comparison) of Total and Unbound Darunavir and Total Cobicistat After Administration of Darunavir/Cobicistat at 800/150 mg Once Daily as Part of anAntiretroviral Regimen, During the 2nd and 3rd Trimester of Pregnancy Compared to Postpartum

Pharmacokinetic Results (Within-Subject Comparison) of Total and Unbound Darunavir and Total Cobicistat After Administration of Darunavir/Cobicistat at 800/150 mg Once Daily as Part of anAntiretroviral Regimen, During the 2nd and 3rd Trimester of Pregnancy Compared to Postpartum - Illustration
Legend: 90% CI: 90% confidence interval; GMR: geometric mean ratio (i.e. second or third trimester / postpartum). Solid vertical line: ratio of 1.0; dotted vertical lines: reference lines of 0.8 and 1.25.

Assessment of Drug Interactions

Drug interaction trials were conducted with TYBOST (as a single entity) and desipramine, digoxin, and efavirenz. Drug interaction trials of TYBOST coadministered with atazanavir or darunavir included atorvastatin, drospirenone/ethinyl estradiol, and rosuvastatin. Drug interaction trials of TYBOST coadministered with elvitegravir included rosuvastatin and rifabutin.

The effects of cobicistat on the exposure of coadministered drugs are shown in Table 11.

Table 11 Drug Interactions: Changes in Pharmacokinetic Parameters forCoadministered Drugs in the Presence of Cobicistata
Note: The information listed below is not a comprehensive list of all the available drug interaction data for concomitant medications with cobicistat containing regimens. Please refer to the U.S. prescribing information for antiretroviral medications administered in combination with cobicistat for additional drug interaction information.

Coadministered Drug Dose of Coadministered Drug (mg) TYBOST Dose (mg) N Mean Ratio of Coadministered Drug PharmacokineticParameters (90% CI);
No effect = 1.00
Cmax AUC
Atorvastatin 10 single dose 150 once daily 16 18.85b
(13.53, 26.27)
9.22b
(7.58, 11.22)
4.19c
(3.67, 4.78)
3.90c
(3.52, 4.32)
Desipramine 50 single dose 150 once daily 8 1.24
(1.08, 1.44)
1.65
(1.36, 2.02)
Digoxin 0.5 single dose 150 once daily 22 1.41
(1.29, 1.55)
1.08
(1.00, 1.17)
Drospirenone/ ethinyl estradiol 3 drospirenone single dose 150 once daily 14 1.12b
(1.05, 1.19)
2.30b
(2.00, 2.64)
0.02 ethinyl estradiol single dose 0.82b
(0.76, 0.89)
0.78b
(0.73, 0.85)
3 drospirenone single dose 150 once daily 15 1.15c
(1.05, 1.26)
1.58c
(1.47, 1.71)
0.02 ethinyl estradiol single dose 0.86c
(0.77, 0.95)
0.70c
(0.63, 0.77)
Efavirenz 600 single dose 150 once daily 17 0.87
(0.80, 0.94)
0.93
(0.89, 0.97)
Rosuvastatin 10 single dose 150 once daily 16 10.58b
(8.72, 12.83)
3.42b
(2.87, 4.07)
3.77c
(3.29, 4.32)
1.93c
(1.70, 2.20)
a. All interaction studies conducted in healthy subjects.
b. Study conducted in the presence of 300 mg atazanavir.
c. Study conducted in the presence of 800 mg darunavir.

Microbiology

Antiviral Activity

Cobicistat does not inhibit recombinant HIV-1 protease in a biochemical assay and has no detectable antiviral activity in cell culture against HIV-1, HBV, or HCV. The antiviral activity in cell culture of selected HIV-1 antiretroviral drugs was not antagonized by cobicistat.

Resistance

In an analysis of treatment-failure adult subjects who received TYBOST coadministered with atazanavir and TRUVADA in Trial 114 through Week 144, evaluable genotypic data from paired baseline and treatment-failure isolates from subjects who had HIV-1 RNA greater than or equal to 400 copies/mL were available for all 21 virologic failures in the TYBOST group (6%, 21/344). Among the 21 subjects, 3 developed the emtricitabine resistance-associated substitution M184V. No subject developed the tenofovir resistance-associated substitution K65R or K70E, or any primary resistance substitution associated with protease inhibitors. In the ritonavir group, evaluable genotypic data were available for all 19 virologic failures (5%, 19/348). Among the 19 patients, 1 developed the emtricitabine resistance-associated substitution M184V with no tenofovir or protease inhibitor resistance-associated substitutions.

In an as-treated analysis of pediatric subjects between the ages of 12 to less than 18 years who received TYBOST coadministered with atazanavir or darunavir plus two NRTIs in Trial 128, 3 of 20 subjects qualified for resistance analysis through Week 48; all 3 subjects were receiving TYBOST coadministered with atazanavir and 1 had evaluable data and no significant resistance-associated substitutions in protease or reverse transcriptase [see Clinical Studies].

Clinical Studies

Clinical Trial Results In HIV-1 Infected Treatment-Naïve Adult Subjects –Trial 114

The activity of TYBOST as a CYP3A inhibitor to increase the systemic exposures of atazanavir or darunavir has been demonstrated in pharmacokinetic trials. In these trials, the exposure of atazanavir or darunavir coadministered with TYBOST 150 mg was consistent with those observed with ritonavir 100 mg [see CLINICAL PHARMACOLOGY]. For clinical efficacy of darunavir/ritonavir 800/100 mg once daily, refer to the prescribing information for darunavir.

The safety and efficacy of TYBOST coadministered with atazanavir were evaluated in a randomized, double-blind, active-controlled trial (Trial 114) in HIV-1 infected treatmentnaïve subjects with baseline estimated creatinine clearance above 70 mL/min (N=692). In Trial 114, subjects were randomized in a 1:1 ratio to receive either atazanavir 300 mg + TYBOST 150 mg once daily or atazanavir 300 mg + ritonavir 100 mg once daily. All subjects received concomitant treatment with 300 mg of TDF and 200 mg of emtricitabine once a day administered as single tablet TRUVADA. Randomization was stratified by screening HIV-1 RNA level (≤100,000 copies/mL or >100,000 copies/mL).

The mean age of subjects was 37 years (range 19–70); 83% were male, 60% were White, 18% were Black, and 12% were Asian. The mean baseline plasma HIV-1 RNA was 4.8 log10 copies/mL (range 3.2–6.4). Forty percent of patients had baseline viral loads >100,000 copies/mL. The mean baseline CD4+ cell count was 352 cells/mm3 (range 1–1455) and 17% had CD4+ cell counts ≤200 cells/mm3.

Virologic outcomes in Trial 114 through Week 144 are presented in Table 12. In Trial 114, the mean increase from baseline in CD4+ cell count at Week 144 was 281 cells/mm3 in the TYBOST group and 297 cells/mm3 in the ritonavir group.

Table 12 Virologic Outcome of Randomized Treatment of Trial 114 in HIV-1 Infected Treatment Naïve Adults at Week 144a

  TYBOST + Atazanavir + TRUVADA
(N=344)
Ritonavir + Atazanavir + TRUVADA
(N=348)
HIV-1 RNA <50 copies/mL 72% 74%
  Treatment Difference −2.1% (95% CI = −8.7%, 4.5%)
HIV RNA ≥50 copies/mLb 8% 5%
No Virologic Data at Week 144 Window 20% 21%
  Discontinued Study Drug Due to AE or Deathc 11% 11%
  Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA <50 copies/mLd 8% 10%
  Missing Data During Window but on Study Drug <1% <1%
a. Week 144 window was between Day 967 and 1050 (inclusive).
b. Included subjects who had ≥50 copies/mL in the Week 144 window; subjects who discontinued early due to lack or loss of efficacy; subjects who discontinued for reasons other than an adverse event (AE), death, or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥50 copies/mL.
c. Includes subjects who discontinued due to AE or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.
d. Includes subjects who discontinued for reasons other than an AE, death, or lack or loss of efficacy; e.g., withdrew consent, lost to follow-up, etc.

Clinical Trial Results In HIV-1 Infected Virologically Suppressed Pediatric Subjects – Trial 128

Trial 128 was a Phase 2/3 multicenter, open-label trial to evaluate the pharmacokinetics, safety, and efficacy of TYBOST coadministered with atazanavir or darunavir in HIV-1 infected virologically suppressed pediatric subjects ages 12 years and older with baseline estimated creatinine clearance ≥90 mL/min/1.73 m2. Subjects were on a stable antiretroviral regimen (for at least 3 months), consisting of atazanavir or darunavir, both administered with ritonavir, combined with 2 nucleotide reverse transcriptase inhibitors (NRTIs). They were switched from ritonavir to TYBOST 150 mg once daily and continued atazanavir (N=14) or darunavir once daily (N=7) and 2 NRTIs.

The mean age of subjects was 14 years (range 12–17 years); median weight was 55 kg; 62% were male, 38% were Asian, 33% were White, 19% were Black, and 67% were not Hispanic or Latino. At baseline, 20/21 subjects had plasma HIV-1 RNA <50 copies/mL and 1 subject had plasma HIV-1 RNA of 50 copies/mL.

In subjects who switched to TYBOST coadministered with atazanavir, 93% (13/14) of subjects remained suppressed (HIV-1 RNA <50 copies/mL), and 1 subject experienced virologic failure at Week 48. From a median baseline CD4+ cell count and CD4+% of 770 cells/mm3 (range 486 to 1765 cells/mm3) and 33% (range 23% to 45%), respectively, the median change from baseline in CD4+ cell count and CD4+% at Week 48 was -60 cells/mm3 (range -500 to 705 cells/mm3) and -0.3% (range -6% to 8%), respectively.

In subjects who switched to TYBOST coadministered with darunavir, 86% (6/7) of subjects remained suppressed (HIV-1 RNA <50 copies/mL), and 1 subject had missing data at Week 48. From a median baseline CD4+ cell count and CD4+% of 1117 cells/mm3 (range 658 to 2416 cells/mm3) and 45% (range 28% to 56%), respectively, the median change from baseline in CD4+ cell count and CD4+% at Week 48 was -342 cells/mm3 (range -1389 to 219 cells/mm3) and -6% (range -12% to 5%), respectively. All 6 subjects with available data had CD4+ cell counts above 800 cells/mm3 at Week 48.

Medication Guide

PATIENT INFORMATION

TYBOST®
(TYE-bost)
(cobicistat) tablets

Important: Ask your healthcare provider or pharmacist about medicines that should not be taken with TYBOST. For more information, see the section “What should I tell my healthcare provider before taking TYBOST?”

Read this Patient Information before you start taking TYBOST and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment.

Also read the Patient Information for atazanavir or darunavir prescribed by your healthcare provider when taking TYBOST.

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 only.
  • 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.

Do not take TYBOST combined with atazanavir or darunavir if you also take a medicine that contains:

  • alfuzosin hydrochloride
  • carbamazepine
  • cisapride
  • colchicine, if you have liver or kidney problems
  • dronedarone hydrochloride
  • ergot-containing medicines:
    • dihydroergotamine mesylate
    • ergotamine tartrate
    • methylergonovine maleate
  • lomitapide
  • lovastatin
  • lurasidone
  • midazolam, when taken by mouth
  • phenobarbital
  • phenytoin
  • pimozide
  • ranolazine
  • rifampin
  • sildenafil, when used for treating the lung problem pulmonary arterial hypertension (PAH)
  • simvastatin
  • St. John’s wort (Hypericum perforatum) or a product that contains St. John’s wort
  • triazolam

Do not take TYBOST with atazanavir if you also take a medicine that contains:

  • drospirenone/ethinyl estradiol
  • indinavir
  • irinotecan
  • nevirapine

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.
      Pregnancy Registry: There is a pregnancy registry for women 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. Do not breastfeed if you take TYBOST.
    • You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.
  • It is not known if TYBOST can pass to your baby in your breast milk.

Talk to your healthcare provider about the best way to feed your baby.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, 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. Taking TYBOST with atazanavir ordarunavir, along with certain other medicines can lead to severe or life-threatening side effects, or could lead todeath. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a newmedicine.

  • You can ask your healthcare provider or pharmacist for a list of medicines that interact when taken with TYBOST with atazanavir or darunavir.
  • Do not start a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take TYBOST with atazanavir or darunavir, along with other medicines.

How should I take TYBOST?

  • Take TYBOST exactly as your healthcare provider tells you.
  • Do not change your dose or stop taking TYBOST without first talking with your healthcare provider.
  • Stay under the care of your healthcare provider during treatment with TYBOST. See your healthcare provider regularly while taking TYBOST.
  • Take TYBOST 1 time each day at the same time you take atazanavir or darunavir. It is important to take these medicines on a regular dosing schedule.
  • Take TYBOST with atazanavir or TYBOST with darunavir, along with food.
  • If you take too much TYBOST, call your healthcare provider or go to the nearest hospital emergency room right away.
  • Do not run out of TYBOST. The virus in your blood may become resistant to the HIV-1 medicine atazanavir or darunavir if TYBOST is stopped for even a short time. When your supply starts to run low, get more from your healthcare provider or pharmacy.

What are the possible side effects of TYBOST?

TYBOST when taken with certain other medicines can cause new or worse kidney problems, including kidney failure. Your healthcare provider should check your kidneys before you start and while you are taking TYBOST.

The most common side effects of TYBOST with atazanavir include yellowing of the skin and rash.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of TYBOST. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store TYBOST?

  • Store TYBOST at room temperature between 68°F to 77°F (20°C to 25°C).
  • TYBOST comes in a child-resistant container.
  • Do not use TYBOST if the seal over the bottle opening is broken or missing.
  • Keep TYBOST in its original container.
  • Keep the container tightly closed.

Keep TYBOST and all medicines out of reach of children.

General information about the safe and effective use of TYBOST.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use TYBOST for a condition for which it was not prescribed. Do not give TYBOST to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about TYBOST that is written for health professionals.

What are the ingredients in TYBOST?

Active ingredient: cobicistat

Inactive ingredients: silicon dioxide, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The tablets are film-coated with a coating material containing polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, sunset yellow FCF (FD&C Yellow #6) aluminum lake, and iron oxide yellow.

Manufactured and distributed by: Gilead Sciences, Inc. Foster City, CA 94404 © 2019 Gilead Sciences, Inc. All rights reserved. TYBOST, GSI, and TRUVADA are trademarks of Gilead Sciences, Inc., or its related companies. All other trademarks are the property of their respective owners. 203094-GS-007 For more information, call 1-800-445-3235 or go to www.GILEAD.com

This Patient Information has been approved by the U.S. Food and Drug Administration.

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Report Problems to the Food and Drug Administration

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.

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