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Drug Interactions Between Integrase Strand Transfer Inhibitors and Other Drugs

(Last updated:5/1/2014; last reviewed:5/9/2015)

This table provides information on known or predicted PK interactions between INSTIs and non-ARV drugs. The table includes information on interactions with EVG, an INSTI that is available in two formulations:

  1. A fixed-dose combination tablet of EVG/c/TDF/FTC indicated for use as a single-tablet regimen
  2. A stand-alone tablet indicated for use with a RTV-boosted PI (PI/r) and other ARVs in ARV treatmentexperienced patients.

In the table, the drug interactions with EVG/c/TDF/FTC and those with EVG plus (PI/r) are presented separately. For several interactions, no dose adjustment is necessary for EVG when given with a concomitant drug; however, since EVG should always be given with a PI/r, clinicians should refer to Table 19a for recommendations on the management of drug interactions resulting from the PI/r used with EVG.

Table 19d. Drug Interactions Between Integrase Strand Transfer Inhibitors and Other Drugs
Concomitant Drug Class/Name
INSTI
Effect on INSTI or Concomitant Drug Concentrations
Dosing Recommendations and Clinical Comments
Acid Reducers
Aluminium, Magnesium 
+/- 
Calcium Containing Antacids

Please refer to the Miscellaneous Interactions section below for recommendations on use with other polyvalent cation products (e.g., iron, calcium supplements, multivitamins).
DTG DTG AUC ↓ 74% if given simultaneously; DTG AUC ↓ 26% if given 2 hours before antacid  Give DTG at least 2 hours before or at least 6 hours after medications containing polyvalent cations.
EVG/cobi/TDF/FTC
EVG AUC ↓ 40% to 50% if given simultaneously, ↓ 15% to 20% if given 2 hours before or after antacid; ↔ with 4-hour interval
Separate EVG/cobi/FTC/TDF and antacid administration by more than 2 hours.
EVG plus (PI/r)

• EVG AUC ↓ 40% to 50% if given simultaneously with antacid;

• EVG AUC ↓ 15% to 20% if antacid given 2 hours before or after EVG; <-> with 4-hour interval

Separate EVG and antacid administration by more than 2 hours.
RAL Al-Mg Hydroxide Antacid
RAL Cmin ↓ 54% to 63% if given simultaneously or 2 hours before or after antacid

CaCO3 Antacid
RAL AUC ↓ 54%, Cmin ↓ 32%
Do not co-administer RAL and Al-Mg hydroxide antacids. Use alternative acid reducing agent.

No dosing separation necessary when co-administering RAL and CaCO3 antacids.
H2-Receptor Antagonists EVG/cobi/TDF/FTC No significant effect No dosage adjustment necessary.
EVG plus (PI/r) <-> EVG No dosage adjustment necessary for EVG. Refer to Table 19a for information on PI/r interactions.
PPIs DTG No significant effect No dosage adjustment necessary.
EVG/cobi/TDF/FTC No significant effect No dosage adjustment necessary.
EVG plus (PI/r) <-> EVG No dosage adjustment necessary for EVG. Refer to Table 19a for information on PI/r interactions.
RAL RAL AUC ↑ 212%, Cmin ↑ 46%  No dosage adjustment necessary.
Anticoagulants and Antiplatelets
Apixaban • EVG/c/TDF/FTC • EVG plus (PI/r) ↑ apixaban expected Avoid concomitant use.
Dabigatran • EVG/c/TDF/FTC • EVG plus (PI/r) ↑ dabigatran possible No dosage adjustment for dabigatran if CrCl >50 mL/min. Avoid coadministration if CrCl <50 mL/min.
Rivaroxaban • EVG/c/TDF/FTC • EVG plus (PI/r) ↑ rivaroxaban expected Avoid concomitant use.
Ticagrelor • EVG/c/TDF/FTC • EVG plus (PI/r) ↑ ticagrelor expected Avoid concomitant use.
Vorapaxar • EVG/c/TDF/FTC • EVG plus (PI/r) ↑ vorapaxar expected Avoid concomitant use.
Warfarin

• EVG/c/TDF/FTC

• EVG plus (PI/r)

No data: but warfarin levels may be affected Monitor INR and adjust warfarin dose accordingly.
Anticonvulsants
Carbamazepine
Oxcarbazepine
Phenobarbital
Phenytoin
DTG DTG possible
Consider alternative anticonvulsant.
EVG/cobi/TDF/FTC ↑ carbamazepine possible
↓ EVG possible
↓ cobi possible
Consider alternative anticonvulsant.
EVG plus (PI/r) ↓ EVG Consider alternative anticonvulsant
Ethosuximide

• EVG/cobi/TDF/FTC

• EVG plus (PI/r)

↑ ethosuximide possible Clinically monitor for ethosuxamide toxicities.
Antidepressants/Anxiolytics/Antipsychotics Also see Sedative/Hypnotics section below.
Bupropion EVG/c/TDF/FTC ↑ or ↓ bupropion possible Titrate bupropion dose based on clinical response.
EVG plus (PI/r) ↓ bupropion possible Titrate bupropion dose based on clinical response.
Buspirone

EVG/c/TDF/FTC

• EVG plus (PI/r)

↑ buspirone possible Initiate buspirone at a low dose. Dose reduction may be necessary.
Fluvoxamine

• EVG/c/TDF/FTC

• EVG plus (PI/r)

↑ or ↓ EVG possible Consider alternative antidepressant or ARV.
Quetiapine

• EVG/c/TDF/FTC
• EVG plus (PI/r)

↑ quetiapine AUC expected.

Initiation of quetiapine in a patient receiving EVG/c/TDF/FTC:

• Start quetiapine at the lowest dose and titrate up as needed. Monitor for quetiapine efficacy and adverse effects.

Initiation of EVG/c/TDF/FTC in a patient receiving a stable dose of quetiapine:

• Reduce quetiapine dose to 1/6 of the original dose, and closely monitor for quetiapine efficacy and adverse effects.

SSRIs

Citalopram

Escitalopram

Fluoxetine

Paroxetine

Sertraline

EVG/cobiTDF/FTC ↑ SSRI possible Initiate with lowest dose of SSRI and titrate dose carefully based on antidepressant response.
EVG plus (PI/r) ↑ or ↓ SSRI possible Titrate SSRI dose based on clinical response.

TCAs

Amitriptyline

Desipramine

Doxepin

Imipramine

Nortriptyline

EVG/cobi/TDF/FTC Desipramine AUC ↑ 65% Initiate with lowest dose and titrate dose of TCA carefully.
EVG plus (PI/r) ↑ TCA expected Initiate with lowest dose of TCA and titrate dose carefully based on antidepressant response and/or drug levels.
Trazodone

• EVG/cobi/TDF/FTC

• EVG plus (PI/r)

↑ trazodone possible Initiate with lowest dose and titrate dose of trazodone carefully.
Antifungals
Itraconazole EVG/cobi/TDF/FTC ↑ itraconazole expected
↑ EVG and cobi possible
Consider monitoring itraconazole level to guide dosage adjustments. High doses (>200 mg/day) are not recommended unless dose is guided by itraconazole levels.
EVG plus (PI/r) ↑ EVG possible Refer to Table 19a for PI recommendations.
Posaconazole EVG/cobi/TDF/FTC ↑ EVG and cobi possible
↑ posaconazole possible
If co-administered, monitor posaconazole concentrations 
EVG plus (PI/r) ↑ EVG possible Refer to Table 19a for PI recommendations.
Voriconazole EVG/cobi/TDF/FTC ↑ voriconazole expecte
↑ EVG and cobi possible
Risk/benefit ratio should be assessed to justify use of voriconazole. If administered, consider monitoring voriconazole level. Adjust dose accordingly.
EVG plus (PI/r) Changes in voriconazole and EVG possible Refer to Table 19a for PI recommendations.
Antimycobacterials
Clarithromycin EVG/cobi/TDF/FTC ↑ clarithromycin possible
↑ cobi possible
CrCl ≥60 mL/min
No dose adjustment is necessary.

CrCl 50−60 mL/min:
Reduce clarithromycin dose by 50%.

CrCl <50 mL/min:
EVG/cobi/TDF/FTC is not recommended.
Rifabutin DTG Rifabutin (300 mg once daily):
DTG AUC ↔, Cmin 30%
No dosage adjustment necessary.
EVG/cobi/TDF/FTC Compared with rifabutin (300 mg daily) administered alone, when rifabutin (150 mg every other day) administered with EVG/cobi/TDF/FTC, no significant change in rifabutin AUC; 

For 25-O-desacetyl-rifabutin, AUC ↑ 625% 

EVG AUC 21%, Cmin 67%
Do not co-administer.
EVG plus (PI/r)

• <-> EVG

• <-> rifabutin AUC

• 25-O-desacetyl-rifabutin AUC ↑ 951%

Refer to Table 19a for dosing recommendations for rifabutin with PI.
RAL RAL AUC ↑ 19%, Cmin ↓ 20% No dosage adjustment necessary.
Rifampin DTG Rifampin with DTG 50 mg BID Compared with DTG 50 mg BID Alone
DTG AUC ↓ 54%, Cmin ↓ 72%

Rifampin with DTG 50 mg BID Compared with DTG 50 mg Once Daily Alone
DTG AUC ↑ 33%, Cmin ↑ 22%

Dose:

DTG 50 mg BID (instead of 50 mg once daily) for patients without suspected or documented INSTI mutation. 

Alternative to rifampin should be used in patients with certain suspected or documented INSTI-associated resistance substitutions. Consider using rifabutin.

  • EVG/cobi/TDF/FTC
  • EVG plus (PI/r)
Significant ↓ EVG and cobi expected Do not co-administer.
RAL RAL 400 mg
RAL AUC ↓ 40%, Cmin ↓ 61% 

Compared with RAL 400 mg BID Alone, Rifampin with RAL 800 mg BID
RAL AUC ↑ 27%, Cmin ↓ 53% 
Dose: RAL 800 mg BID
Monitor closely for virologic response or consider using rifabutin as an alternative rifamycin
Rifapentine DTG Significant ↓ DTG expected Do not co-administer.
  • EVG/cobi/TDF/FTC
  • EVG plus (PI/r)
Significant ↓ EVG and cobi expected Do not co-administer.
RAL RAL Cmin ↓ 41% Do not co-administer.
Benzodiazepines
Clonazepam
Clorazepate
Diazepam
Estazolam
Flurazepam
EVG/cobi/TDF/FTC ↑ benzodiazepines possible Dose reduction of benzodiazepine may be necessary. Initiate with low dose and clinically monitor.

Consider alternative benzodiazepines to diazepam, such as lorazepam, oxazepam, or temazepam.
Midazolam
Triazolam
DTG DTG 25 mg
midazolam AUC ↔
No dosage adjustment necessary.
EVG/cobi/TDF/FTC ↑ midazolam expected
↑ triazolam expected
Do not co-administer triazolam or oral midazolam and EVG/cobi/TDF/FTC.

Parenteral midazolam can be used with caution in a closely monitored setting. Consider dose reduction, especially if more than one dose is administered.
Cardiac Medications
Anti-Arrhythmics

Amiodarone, bepridil, digoxin, disopyramide, dronedarone, flecainide, systemic lidocaine, mexilitine, propafenone, quinidine
EVG/cobi/TDF/FTC ↑ anti-arrhythmics possible

digoxin Cmax ↑ 41%, AUC no significant change
Use anti-arrhythmics with caution. Therapeutic drug monitoring, if available, is recommended for anti- arrhythmics.
EVG plus (PI/r) ↑ anti-arrhythmics possible Refer to Table 18 and 19a for use of anti-arrhythmics and PI/r
Bosentan EVG/cobi/TDF/FTC ↑ bosentan possible In Patients on EVG/cobi/FTC/TDF ≥10 Days
Start bosentan at 62.5 mg once daily or every other day based on individual tolerability. 

In Patients on Bosentan who Require EVG/cobi/FTC/TDF
Stop bosentan ≥36 hours before EVG/cobi/FTC/TDF initiation. After at least 10 days following initiation of EVG/cobi/FTC/TDF, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability.
EVG plus (PI/r) ↑ bosentan possible Refer to Table 19a for recommendations on bosentan dosing when used with PI/r.

Beta-blockers

(eg. metoprolol, timolol)

EVG/cobi/TDF/FTC

EVG plus (PI/r)

↑ beta-blockers possible

Beta-blocker dose may need to be decreased; adjust dose based on clinical response.

Consider using beta-blockers that are not metabolized by CYP450 enzymes (e.g., atenolol, labetalol, nadolol, sotalol).

Dofetilide
DTG ↑ dofetilide expected
Do not co-administer.
CCBs
  • EVG/cobi/TDF/FTC
  • EVG plus (PI/r)
↑ CCBs possible

Co-administer with caution. Titrate CCB dose and monitor for CCB efficacy and toxicities.

Refer to Table 19a for diltiazem plus ATV/r and SQV/r recommendations.

Corticosteroids
Dexamethasone

EVG/cobi/TDF/FTC

↓ EVG and COBI possible

Use systemic dexamethasone with
caution. Monitor virologic response to
EVG plus (PI/r) ↓ EVG possible ART. Consider alternative corticosteroid

 

EVG plus (PI/r)

↓ EVG possible

Use systemic dexamethasone with
caution. Monitor virologic response to
EVG plus (PI/r) ↓ EVG possible ART. Consider alternative corticosteroid

Fluticasone
Inhaled/Intranasal
  • EVG/cobi/TDF/FTC
  • EVG plus (PI/r)
↑ fluticasone possible Co-administration may result in adrenal insufficiency, including Cushing’s syndrome. Consider alternative therapy (e.g., beclomethasone), particularly for long-term use.
Methylprednisolone, Prednisolone, Triamcinolone 
Local injections, including intra-articular, epidural, intra-orbital

 

  • EVG/cobi/TDF/FTC
  • EVG plus (PI/r)

 

↑ glucocorticoids expected
Co-administration may result in adrenal insufficiency, including Cushing’s syndrome. Do not co-administer.

Consider alternative non-steroidal therapies. If intra-articular corticosteroid therapy required, change to alternative non-CYP3A-modulating ART (e.g., RAL, DTG).
Hepatitis C Direct Acting Antivirals
Boceprevir DTG DTG AUC ↔
No dosage adjustment necessary.
EVG/cobi/TDF/FTC No data Do not co-administer.
EVG plus (PI/r) ↓ boceprevir Do not co-administer
RAL No significant effect No dosage adjustment necessary.
Simeprevir EVG/cobi/TDF/FTC ↑ simeprevir expected
Co-administration is not recommended.
EVG plus (PI/r) <-> EVG expected Co-administration is not recommended.
RAL No significant effect
No dosage adjustment necessary.
Dasabuvir plus plus Ombitasvir/Paritaprevir/r RAL RAL AUC ↑ 134%
No dosage adjustment necessary.
DTG No data No dosing recommendations at this time.
  • EVG plus (PI/r)
  • EVG/c/TDF/FTC
No data Do not co-administer.
Ledipasvir/Sofosbuvir EVG/c/TDF/FTC ↑ TDF and ↑ ledipasvir expected Do not co-administer.
EVG plus (PI/r) <->EVG expected Refer to Table 19a for PI dosing recommendations.
Sofosbuvir All INSTIs No significant effect expected No dosage adjustment necessary.
Herbal Products
St. John’s Wort DTG ↓ DTG possible
Do not co-administer.

• EVG/c/TDF/FTC

• EVG plus (PI/r)

↓ EVG and COBI possible Do not co-administer.
Hormonal Contraceptives
Hormonal Contraceptives RAL No clinically significant effect No dosage adjustment necessary.
Norgestimate/ethinyl estradiol DTG No significant effect
No dosage adjustment necessary.
EVG/cobi/TDF/FTC Norgestimate AUC, Cmax, Cmin ↑ >2-fold

Ethinyl estradiol AUC ↓ 25%, Cmin ↓ 44%
The effects of increases in progestin (norgestimate) are not fully known and can include insulin resistance, dyslipidemia, acne, and venous thrombosis. Weigh the risks and benefits of the drug, and consider alternative contraceptive method.
EVG plus (PI/r) <-> EVG Refer to Table 19a for recommendations when used with PI/r.
HMG-CoA Reductase Inhibitors
Atorvastatin EVG/cobi/TDF/FTC ↑ atorvastatin possible Titrate statin dose slowly and use the lowest dose possible.
EVG plus (PI/r) <-> EVG expected Refer to Table 19a for dosing recommendations when used with PI/r.
Lovastatin
  • EVG/cobi/TDF/FTC
  • EVG plus (PI/r)
Significant ↑ lovastatin expected Contraindicated. Do not co-administer.
Pitavastatin
Pravastatin
EVG/cobi/TDF/FTC No data No dosage recommendation
EVG plus (PI/r) <-> EVG expected Refer to Table 19a for dosing recommendations when used with PI/r.
Rosuvastatin EVG/cobi/TDF/FTC Rosuvastatin AUC ↑ 38%, Cmax ↑ 89% Titrate statin dose slowly and use the lowest dose possible.
EVG plus (PI/r) <-> EVG expected Refer to Table 19a for dosing recommendations when used with PI/r.
Simvastatin EVG/cobi/TDF/FTC EVG plus (PI/r) Significant ↑ simvastatin expected Contraindicated. Do not co-administer.
Immunosuppressants
Cyclosporine
Everolimus Sirolimus
Tacrolimus
• EVG/c/TDF/FTC • EVG plus (PI/r) ↑ immunosuppressant possible Initiate with an adjusted immunosuppressant dose to account for potential increased concentrations and monitor for toxicities. Therapeutic drug monitoring of immunosuppressant is recommended. Consult with specialist as necessary.
Narcotics/Treatment for Opioid Dependence
Buprenorphine EVG/cobi/TDF/FTC Buprenorphine: AUC ↑ 35%, Cmax ↑ 12%, Cmin ↑ 66%

Norbuprenorphine: AUC ↑ 42%,
Cmax ↑ 24%, Cmin ↑ 57%
No dosage adjustment necessary. Clinical monitoring is recommended.
EVG plus (PI/r) <-> EVG expected Refer to Table 19a for dosing recommendations when used with PI/r.
RAL No significant effect No dosage adjustment necessary.
Methadone DTG No significant effect No dosage adjustment necessary.
EVG/cobi/TDF/FTC No significant effect No dosage adjustment necessary.
EVG plus (PI/r) ↓ methadone Opioid withdrawal unlikely but may occur. Dosage adjustment of methadone is not usually required. Monitor for opioid withdrawal and increase methadone dose as clinically indicated.
RAL No significant effect No dosage adjustment necessary.
Neuroleptics
Perphenazine
Risperidone
Thioridazine
EVG/cobi/TDF/FTC ↑ neuroleptic possible Initiate neuroleptic at low dose. Decrease in neuroleptic dose may be necessary.
PDE5 Inhibitors
Avanafil
  • EVG/cobi/TDF/FTC
  • EVG plus (PI/r)
No data Co-administration is not recommended.
Sildenafil
  • EVG/cobi/TDF/FTC
  • EVG plus (PI/r)
↑ sildenafil expected For Treatment of Erectile Dysfunction:
Start with sildenafil 25 mg every 48 hours and monitor for adverse effects of sildenafil.

For treatment of PAH:
Contraindicated
Tadalafil
  • EVG/cobi/TDF/FTC
  • EVG plus (PI/r)
↑ tadalafil expected For Treatment of Erectile Dysfunction:
Start with tadalafil 5-mg dose and do not exceed a single dose of 10 mg every 72 hours. Monitor for adverse effects of tadalafil.

For Treatment of PAH
In Patients on EVG/cobi/TDF/FTC >7 Days:
Start with tadalafil 20 mg once daily and increase to 40 mg once daily based on tolerability.
In Patients on Tadalafil who Require EVG/cobi/TDF/FTC:
Stop tadalafil ≥24 hours before EVG/cobi/TDF/FTC initiation. Seven days after EVG/cobi/TDF/FTC initiation restart tadalafil at 20 mg once daily, and increase to 40 mg once daily based on tolerability.
Vardenafil
  • EVG/cobi/TDF/FTC
  • EVG plus (PI/r)
↑ vardenafil expected Start with vardenafil 2.5 mg every 72 hours and monitor for adverse effects of vardenafil.
Sedative/Hypnotics
Clonazepam, Clorazepate, Diazepam, Estazolam, Flurazepam
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)
↑ benzodiazepines possible

Dose reduction of benzodiazepine may be necessary. Initiate with low dose and clinically monitor.

Consider alternative benzodiazepines to diazepam, such as lorazepam, oxazepam, or temazepam.

Midazolam

Triazolam

DTG

With DTG 25 mg:

• midazolam AUC <->

No dosage adjustment necessary.
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)

• ↑ midazolam expected

• ↑ triazolam expected

Do not coadminister triazolam or oral midazolam and EVG/c/TDF/FTC or (EVG plus PI).

Parenteral midazolam can be used with caution in a closely monitored setting. Consider dose reduction, especially if more than one dose is administered.

Suvorexant
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)
↑ suvorexant possible Co-administration is not recommended.
Zolpidem
  • EVG/cobi/TDF/FTC
  • EVG plus (PI/r)
↑ zolpidem possible Initiate zolpidem at a low dose. Dose reduction may be necessary.
Miscellaneous Drugs
Colchicine
  • EVG/cobi/TDF/FTC
  • EVG plus (PI/r)
↑ colchicine expected Do not co-administer in patients with hepatic or renal impairment.

For Treatment of Gout Flares:
Colchicine 0.6 mg for 1 dose, followed by 0.3 mg 1 hour later. Do not repeat dose for at least 3 days.

For Prophylaxis of Gout Flares:
If original regimen was colchicine 0.6 mg BID, the regimen should be decreased to 0.3 mg once daily. If regimen was 0.6 mg once daily, the regimen should be decreased to 0.3 mg every other day.

For Treatment of Familial Mediterranean Fever:
Do not exceed colchicine 0.6 mg once daily or 0.3 mg BID.
Metformin
DTG

DTG 50 mg once daily plus metformin:

• Metformin AUC ↑ 79%, Cmax ↑ 66%, and Cmin ↑ 9%

DTG 50 mg BID plus metformin:

• Metformin AUC ↑ 2.4 fold, Cmax ↑ 2 fold, and Cmin ↑ 14%

When starting metformin in patient on DTG, start at low metformin dose and titrate dose to achieve glycemic control and minimize GI symptoms.

When starting/stopping DTG in patient on metformin, dose adjustment of metformin may be necessary to maintain optimal glycemic control and/or minimize GI symptoms.

Polyvalent Cation Supplements

Mg, Al, Fe, Ca, Zn, including multivitamins with minerals

Note: Please refer to the Acid Reducers section in this table for recommendations on use with Al-, Mg-, and Ca-containing antacids.

All INSTIs
  • ↓ INSTI possible
  • DTG <-> when administered with Ca or Fe supplement simultaneously with food

If coadministration is necessary, give INSTI at least 2 hours before or at least 6 hours after supplements containing polyvalent cations, including but not limited to the following products: cationcontaining laxatives; Fe, Ca, or Mg supplements; and sucralfate. Monitor for virologic efficacy.

DTG and supplements containing Ca or Fe can be taken simultaneously with food. Many oral multivitamins also contain varying amounts of polyvalent cations; the extent and significance of chelation is unknown.

Salmeterol
  • EVG/cobi/TDF/FTC
  • EVG plus (PI/r)
↑ salmeterol possible Do not co-administer because of potential increased risk of salmeterol-associated cardiovascular events.

Key to Acronyms: Al = aluminum; ART = antiretroviral therapy; AUC = area under the curve; BID = twice daily; Ca = calcium; CaCO3 = calcium carbonate; CCB = calcium channel blocker; Cmax = maximum plasma concentration; Cmin = minimum plasma concentration; cobi = cobicistat; CrCl = creatinine clearance; DTG = dolutegravir; EVG = elvitegravir; EVG/c/TDF/FTC = elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine; Fe = iron; FTC = emtricitabine; INSTI = integrase strand transfer inhibitor; Mg = magnesium; PAH = pulmonary arterial hypertension; PI/r = ritonavir-boosted protease inhibitor; RAL = raltegravir; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic anti-depressants; TDF = tenofovir disoproxil fumarate; Zn = zinc

 

Drug Interactions Between Integrase Strand Transfer Inhibitors and Other Drugs

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