Darunavir/cobicistat/emtricitabine/tenofovir AF

Name: Darunavir/cobicistat/emtricitabine/tenofovir AF

Adverse Effects

The following includes all grades unless otherwise specified

>10%

Total cholesterol, Grade 2 (17%)

1-10%

Diarrhea (9%)

LDL cholesterol, Grade 2 (9%)

Rash (8%)

Triglycerides, Grade 2 (7%)

Nausea (6%)

Elevated glucose levels, Grade 2 (6%)

LDL cholesterol, Grade 3 (5%)

Fatigue (4%)

Creatinine, Grade 2 (4%)

Headache (3%)

Abdominal discomfort (2%)

Flatulence (2%)

Total cholesterol, Grade 3 (2%)

Triglycerides, Grade 3 (1%)

Warnings

Black Box Warnings

Not approved for the treatment of chronic hepatitis B virus (HBV) infection, and the safety and efficacy have not been established in patients coinfected with HIV-1 and HBV

Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate (tenofovir DF), and may occur with discontinuation of tenofovir AF

Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue ARTs

If appropriate, initiation of antihepatitis B therapy may be warranted

Contraindications

Alfuzosin: Potential for increased alfuzosin concentrations when coadministered with cobicistat, which can result in serious or life-threatening reactions (eg, hypotension)

Dronedarone: Potential for increased dronedarone concentrations

Strong CYP inducers (rifampin, carbamazepine, phenobarbital, phenytoin, St. John’s wort): Coadministration with CYP inducers may cause a significant decrease in the plasma concentrations of darunavir or cobicistat and result in loss of therapeutic effect and lead to development of resistance

Ergot derivatives (dihydroergotamine, ergotamine, methylergonovine): Potential for serious and/or life-threatening reactions (eg, acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues) when coadministered with cobicistat

Cisapride, lurasidone, pimozide: Potential for serious and/or life-threatening reactions (eg, cardiac arrhythmias) when coadministered with cobicistat

Specific HMG-CoA reductase inhibitors (ie, lovastatin, simvastatin): Potential for serious reactions (eg, myopathy, including rhabdomyolysis) when coadministered with cobicistat

Coadministration with lomitapide (increased toxicity)

PDE5 inhibitors (long-term administration [eg, sildenafil as Revatio for PAH]): Potential for sildenafil-associated adverse reactions (eg, visual disturbances, hypotension, priapism, syncope) when coadministered with cobicistat

Triazolam, midazolam PO: These are extensively metabolized by CYP3A4; potential for prolonged or increased sedation or respiratory depression when coadministered with cobicistat

Concomitant administration of cobicistat with ranolazine has potential for serious and/or life-threatening reactions

Concomitant use of cobicistat with colchicine is contraindicated in patients with renal and/or hepatic impairment owing to potential for serious and/or life-threatening reactions

Hepatitis C direct acting antiviral: Coadministration with elbasvir/grazoprevir increases risk of ALT elevations

Antianginal and antiarrhythmic drugs: Ivabradine

Opioid antagonists: Naloxegol

Cautions

Severe, acute exacerbation of hepatitis B in patients coinfected with HBV and HIV-1 reported (see Black Box Warnings and Dosing Considerations)

Drug-induced hepatitis (eg, acute hepatitis, cytolytic hepatitis) reported in clinical trials with darunavir; patients with preexisting liver dysfunction, including chronic active hepatitis B or C, are at increased risk for liver function abnormalities, including severe hepatic adverse reactions

Rare reports of severe skin reactions, accompanied by fever and/or elevations of transaminases; Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis have been reported

Immune reconstitution syndrome reported in patients treated with combination antiretroviral therapy; autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) reported

Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), reported with use of tenofovir prodrugs

Darunavir contains a sulfonamide moiety; monitor patients with a known sulfonamide allergy after initiating

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, reported with the use of nucleoside analogs, including emtricitabine

New-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia reported during postmarketing surveillance in HIV-infected patients receiving HIV protease inhibitor therapy

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance, observed in patients receiving ARTs

Reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with HIV protease inhibitors

Drug interaction overview

  • Also see Contraindications
  • Symtuza is a complete regimen for HIV-1 infection, and coadministration with other ARTs is not recommended
  • May interact with many drugs; therefore, inform patients of the potential serious drug interactions and that some drugs are contraindicated, while other drugs may require dosage adjustment
  • CYP3A4 inhibitors or inducers
    • Darunavir is metabolized by CYP3A
    • Cobicistat is metabolized by CYP3A and, to a minor extent, by CYP2D6
    • Coadministration of drugs that induce CYP3A activity are expected to increase the clearance of darunavir and cobicistat, resulting in lowered plasma concentrations, which may lead to loss of therapeutic effect and development of resistance
    • Coadministration drugs that inhibit CYP3A may result in increased plasma concentrations of darunavir and cobicistat
  • Potential for other drugs to affect Symtuza
    • Tenofovir AF is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3
    • Drugs that strongly affect P-gp activity may lead to changes in tenofovir AF absorption
    • Drugs that induce P-gp activity are expected to decrease the absorption of tenofovir AF, resulting in decreased plasma concentrations of tenofovir AF, which may lead to loss of therapeutic effect of Symtuza and development of resistance
    • Coadministration of Symtuza with drugs that inhibit P-gp may increase the absorption and plasma concentrations of tenofovir AF
  • Drugs affecting renal function
    • Emtricitabine and tenofovir are primarily excreted by the kidneys via glomerular filtration and active tubular secretion
    • Coadministration of Symtuza with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of emtricitabine, tenofovir, and other renally eliminated drugs, and may increase risk of adverse effects
    • Examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides, and high-dose or multiple NSAIDs

Pregnancy

Pregnancy

Not recommended during pregnancy because of substantially lower exposures of darunavir and cobicistat during pregnancy

Do not initiate Symtuza in pregnant women; switch to an alternant regimen for women who become pregnant during therapy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to to ARTs during pregnancy; clinicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263

Lactation

The CDC recommends that HIV-infected mothers in the United States are not to breastfeed their infants to avoid risking postnatal HIV-1 infection transmission

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Pharmacology

Mechanism of Action

Darunavir: Protease inhibitor; selectively inhibits cleavage of Gag-Pol polyprotein precursors, thereby preventing the formation of mature virus particles

Cobicistat: CYP3A4 inhibitor; mechanism-based pharmaco-enhancer; first product to be developed and submitted solely as pharmacokinetic booster; enhances the systemic exposure of CYP3A substrates (eg, darunavir), where bioavailability is limited and half-life is shortened by CYP3A-dependent metabolism

Emtricitabine: Nucleoside reverse transcriptase inhibitor (NRTI); following phosphorylation, interferes with HIV viral DNA polymerase and inhibits viral replication; cytosine analogue

Tenofovir alafenamide (AF): NRTI prodrug of tenofovir; compared with tenofovir disoproxil fumarate (tenofovir DF, Viread), tenofovir AF is a more targeted form of tenofovir that has demonstrated high antiviral efficacy at a dose that is 10 times lower than tenofovir DF, as well as an improved renal and bone safety profile; inhibits HIV-1 RT by competing with the natural substrate deoxyadenosine 5′-triphosphate and, after incorporation into DNA, by DNA chain termination

Absorption

The bioavailability of the components was not affected when administered PO as a split tablet compared with administration as a tablet swallowed whole

Peak plasma time

  • Darunavir: 3 hr
  • Cobicistat: 3 hr
  • Emtricitabine: 1.5 hr
  • Tenofovir AF: 0.5 hr

Peak plasma concentration, steady-state

  • Darunavir: 8826 ng/mL
  • Cobicistat: 1129 ng/mL
  • Emtricitabine: 2056 ng/mL
  • Tenofovir AF: 163 ng/mL

AUC, steady-state

  • Darunavir: 87,909 ng·hr/mL
  • Cobicistat: 8745 ng·hr/mL
  • Emtricitabine: 11,918 ng·hr/mL
  • Tenofovir AF: 132 ng·hr/mL

Distribution

Protein bound

  • Darunavir: 95%
  • Cobicistat: 97-98%
  • Emtricitabine:

Administration

Oral Administration

Take with food

If unable to swallow the whole tablet, instruct patient to split tablet into 2 pieces using a tablet cutter, and then consume the entire dose immediately after splitting

Storage

Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F)

Keep container tightly closed with desiccant inside to protect from moisture

Dispense only in the original container; keep container tightly closed with desiccant inside to protect from moisture

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