darunavir/cobicistat/emtricitabine/tenofovir AF (Rx)

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%)

<2%

• Gastrointestinal disorders: Dyspepsia, pancreatitis (acute), vomiting
• Skin and subcutaneous tissue disorders: Angioedema, pruritus, Stevens-Johnson syndrome
• Metabolism and nutrition disorders: Anorexia, diabetes mellitus, lipodystrophy
• Reproductive system and breast disorders: Gynecomastia
• Musculoskeletal and connective-tissue disorders: Myalgia, osteonecrosis
• Psychiatric disorders: Abnormal dreams
• Immune system disorders: Drug hypersensitivity, immune reconstitution inflammatory syndrome
• Hepatobiliary disorders: Acute hepatitis

<1%

Creatinine, Grade 4

Triglycerides, Grade 4

Elevated glucose levels, Grade 3

Postmarketing Reports

Metabolism and nutrition disorders: Redistribution of body fat

Musculoskeletal and connective-tissue disorders: Rhabdomyolysis (associated with coadministration with HMG-CoA reductase inhibitors)

Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms

Contraindications

Coadministration of the following drugs due to the potential for serious and/or life-threatening events or loss of therapeutic effect

• Alpha 1-adrenoreceptor antagonist: Alfuzosin
• Anticonvulsants: Carbamazepine, phenobarbital, phenytoin
• Anti-gout: Colchicine, in patients with renal and/or hepatic impairment
• Antimycobacterial: Rifampin
• Antipsychotics: Lurasidone, pimozide
• Cardiac disorders: Dronedarone, ivabradine, ranolazine
• Ergot derivative (eg, dihydroergotamine, ergotamine, methylergonovine)
• GI motility agent: Cisapride
• Herbal product: St. John’s wort (Hypericum perforatum)
• Hepatitis C direct acting antiviral: Elbasvir/grazoprevir
• Lipid modifying agents: Lomitapide, lovastatin, simvastatin
• Opioid Antagonist: Naloxegol
• PDE-5 inhibitor: Sildenafil for treatment of pulmonary arterial hypertension
• Sedatives/hypnotics: Midazolam PO, triazolam

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

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.

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: <4%
• Tenofovir AF: 80%

Blood-to-plasma ratio

• Darunavir: 0.64
• Cobicistat: 0.5
• Emtricitabine: 0.6
• Tenofovir AF: 1

Metabolism

Darunavir: CYP3A

Cobicistat: CYP3A (major); CYP2D6 (minor)

Emtricitabine: Not significantly metabolized; glomerular filtration and active tubular secretion are major elimination routes

Tenofovir AF: Hydrolyzed within cells to form tenofovir (major metabolite) by cathepsin A; minimally metabolized by CYP3A in liver

Elimination

Half-life

• Darunavir: 9.4 hr
• Cobicistat: 3.2 hr
• Emtricitabine: 7.5 hr
• Tenofovir AF: 0.5 hr (tenofovir AF); 44 hr (tenofovir)

Excretion, feces

• Darunavir: 79.5%
• Cobicistat: 86.2%
• Emtricitabine: 13.7%
• Tenofovir AF: 31.7%

Excretion, urine

• Darunavir: 13.9%
• Cobicistat: 8.2%
• Emtricitabine: 70%
• Tenofovir AF: <1%

Oral Administration

Take with food

If unable to swallow the whole tablet, split tablet into 2 pieces using a tablet cutter, and then consume 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