Source: FDA, National Drug Code (US) Revision Year: 2021
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 (7.3) and Clinical Pharmacology (12.3)].
1 These contraindications apply only to TYBOST coadministered with atazanavir
TYBOST decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. This effect should be considered when interpreting changes in estimated creatinine clearance in patients initiating TYBOST, particularly in patients with medical conditions or receiving drugs needing monitoring with estimated creatinine clearance.
Prior to initiating therapy with TYBOST, assess estimated creatinine clearance [see Dosage and Administration (2.3)]. Dosage recommendations are not available for drugs that require dosage adjustments in TYBOST-treated patients with renal impairment [see Adverse Reactions (6.1), Drug Interactions (7.3), and Clinical Pharmacology (12.2)]. Consider alternative medications that do not require dosage adjustments in patients with renal impairment.
Although TYBOST may cause modest increases in serum creatinine and modest declines in estimated creatinine clearance without affecting renal glomerular function, patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL from baseline should be closely monitored for renal safety.
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.
In a clinical trial of TYBOST over 144 weeks (N=692), 10 (2.9%) subjects treated with TYBOST coadministered with atazanavir and TRUVADA and 11 (3.2%) subjects treated with ritonavir coadministered with atazanavir and TRUVADA discontinued study drug due to a renal adverse event. Seven of the 10 subjects (2.0% overall) in the TYBOST group had laboratory findings consistent with proximal renal tubulopathy leading to study drug discontinuation compared to 7 of 11 subjects (2.0% overall) in the ritonavir group. One subject in the TYBOST group had renal impairment at baseline (i.e., estimated creatinine clearance less than 70 mL/min). The laboratory findings in these 7 subjects with evidence of proximal tubulopathy improved but did not completely resolve in all subjects upon discontinuation of TYBOST coadministered with atazanavir and TRUVADA. Renal replacement therapy was not required in any subject.
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 that inhibit or induce CYP3A may respectively increase or decrease concentrations of TYBOST with atazanavir or darunavir.
Increased concentrations may lead to:
Decreased concentrations may lead to:
See Table 6 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7)]. Consider the potential for drug interactions prior to and during TYBOST with atazanavir or darunavir therapy; review concomitant medications during TYBOST with atazanavir or darunavir therapy; and monitor for the adverse reactions associated with concomitant medications [see Contraindications (4) and Drug Interactions (7)].
TYBOST or ritonavir when administered with either atazanavir or darunavir may result in different drug interactions when used with concomitant medications. Complex or unknown mechanisms of drug interactions preclude extrapolation of ritonavir drug interactions to certain TYBOST interactions [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
The following antiretrovirals are not recommended in combination with TYBOST because dosing recommendations for such combinations have not been established and coadministration may result in decreased plasma concentrations of the antiretroviral agents, leading to loss of therapeutic effect and development of resistance:
TYBOST in combination with fixed-dose combination tablets that contain cobicistat is not recommended.
TYBOST in combination with lopinavir/ritonavir or regimens containing ritonavir is not recommended due to similar effects of TYBOST and ritonavir on CYP3A.
The following adverse reaction is described in greater detail in another section of the labeling:
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.
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:
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 Reactions* (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% |
| Rash† | 5% | 4% |
| Ocular icterus | 4% | 2% |
| Nausea | 2% | 2% |
| Diarrhea | 2% | 1% |
| Headache | 2% | 1% |
* Frequencies of adverse reactions are based on Grades 2–4 adverse events attributed to study drugs.
† 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.
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 with 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 Amylase* (>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% |
* 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.
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 (5.1) and Clinical Pharmacology (12.2)]. 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.
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 baseline* | mg/dL | Change from baseline* | |
| 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] |
* 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.
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 (14.2)]. In this trial, the safety profile of TYBOST was similar to that in adults.
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 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.
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).
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 (4), Warnings and Precautions (5.3, 5.4), and Clinical Pharmacology (12.3)].
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 (12.3)].
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 (5.4)].
Evaluate whether dosing adjustments of concomitant medications or coadministered antiretroviral drugs are necessary in:
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 Significant* Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction:
| Concomitant Drug Class: Drug Name | Potential Effect† | 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 H2-Receptor 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 | ↓ 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. |
| Anticonvulsants that are metabolized by CYP3A e.g., clonazepam | ↑ clonazepam | Clinical monitoring of anticonvulsants is recommended. |
| Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs) e.g., paroxetine Tricyclic Antidepressants (TCAs) e.g., amitriptyline desipramine imipramine nortriptyline Other antidepressants: trazodone | 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. |
| Antifungals: itraconazole ketoconazole | ↑ itraconazole ↑ ketoconazole | Specific dosing recommendations are not available for coadministration with itraconazole or ketoconazole. |
| voriconazole | 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) × 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. |
| Antiplatelets: | ||
| ticagrelor | ↑ ticagrelor | Coadministration with ticagrelor is not recommended. |
| clopidogrel | ↓ clopidogrel active metabolite | Coadministration with clopidogrel is not recommended due to potential reduction of the antiplatelet activity of clopidogrel. |
| prasugrel | ↔ prasugrel active metabolite | No dose adjustment is needed when prasugrel is co-administered with TYBOST. |
| 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, excluding cutaneous): 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 Receptor Antagonists: 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: HMG-CoA reductase inhibitors: lovastatin simvastatin | ↑ lovastatin ↑ simvastatin | Coadministration with lovastatin or simvastatin is contraindicated due to potential for serious reactions such as myopathy including rhabdomyolysis. |
| 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 methadone: effects unknown | Initiation of buprenorphine, buprenorphine/naloxone, or methadone in patients taking TYBOST coadministered with atazanavir or darunavir: 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 sildenafil-associated 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. | |
* This table is not all inclusive.
† ↑ = Increase, ↓ = Decrease, ↔ = No change
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.
TYBOST coadministered with darunavir or atazanavir is not recommended during pregnancy [see Dosage and Administration (2.5)]. 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 [see Data and Clinical Pharmacology (12.3)].
TYBOST use during pregnancy has been evaluated in a limited number of individuals as reported by the APR, and available data show no significant 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.
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 [see Clinical Pharmacology (12.3)].
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 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.
Cobicistat was administered orally to pregnant rats at doses of 0, 25, 50, and 125 mg/kg/day on gestation day 6 to 17. Maternal toxicity (adverse clinical signs, decreased body weight and food consumption) was noted at 125 mg/kg/day and was associated with increases in postimplantation loss and decreased fetal weights. No malformations were noted at doses up to 125 mg/kg/day. Systemic exposures (AUC) at 50 mg/kg/day in pregnant females were 1.4-fold higher than the exposures at the MRHD.
In pregnant rabbits, cobicistat was administered orally at doses of 0, 20, 50, and 100 mg/kg/day during the gestation days 7 to 20. No maternal or embryo/fetal effects were noted at the highest dose of 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg/day were 3.3-fold higher than exposures at the MRHD.
In a pre- and postnatal developmental study, cobicistat was administered orally at doses of 0, 10, 30, and 75 mg/kg from gestation day 6 to postnatal day 20, 21, or 22. At doses of 75 mg/kg/day of cobicistat, neither maternal nor developmental toxicity was noted. Systemic exposures (AUC) at this dose were slightly lower than (0.9-fold) the MRHD.
There is no information regarding the presence of cobicistat in human milk, the effects on the breastfed infant, or the effects on milk production. The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV.
TYBOST interacts with certain oral contraceptives [see Drug Interactions (7.3)].
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 virologically suppressed pediatric patients [see Indications and Usage (1.1) and Dosage and Administration (2.2)]:
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 [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)].
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.
Clinical trials of TYBOST did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects.
No dosage adjustment of TYBOST is required in patients with renal impairment, including those with severe renal impairment. No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with severe renal impairment and healthy subjects. TYBOST is coadministered with atazanavir or darunavir; therefore, refer to the prescribing information for atazanavir or darunavir for information regarding dosing recommendations of these drugs in patients with renal impairment [see Clinical Pharmacology (12.3)].
TYBOST has been shown to decrease estimated creatinine clearance without affecting actual renal glomerular function. Dosing recommendations are not available for drugs that require dosing adjustment for renal impairment when used in combination with TYBOST [see Dosage and Administration (2), Warnings and Precautions (5.1), Adverse Reactions (6.1), and Clinical Pharmacology (12.2)].
No dosing adjustment of TYBOST is necessary for patients with mild-to-moderate hepatic impairment. No data are available in patients with severe hepatic impairment. TYBOST is coadministered with atazanavir or darunavir and other antiretroviral drugs; therefore, refer to the prescribing information of these other drugs for information regarding dosing recommendations in patients with hepatic impairment [see Clinical Pharmacology (12.3)].
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