SYMTUZA® (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide)

SYMTUZA® (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide)

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SYMTUZA®

SYMTUZA® (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) is a fixed-dose combination tablet.

  • Darunavir is an inhibitor of the HIV-1 protease.
  • Cobicistat is a mechanism-based inhibitor of cytochrome P450 (CYP) enzymes of the CYP3A family.
  • Emtricitabine, a synthetic nucleoside analog of cytidine, is an HIV nucleoside analog reverse transcriptase inhibitor (HIV NRTI).
  • Tenofovir alafenamide, an HIV NRTI, is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate.

SYMTUZA tablets are for oral administration. Each tablet contains darunavir ethanolate equivalent to 800 mg of darunavir, 150 mg of cobicistat, 200 mg of emtricitabine, and 11.2 mg of tenofovir alafenamide fumarate equivalent to 10 mg of tenofovir alafenamide. The tablets include the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, and microcrystalline cellulose. The tablets are film-coated with a coating material containing polyethylene glycol (macrogol), polyvinyl alcohol (partially hydrolyzed), talc, titanium dioxide, and yellow ferric oxide.

Darunavir: Darunavir, in the form of darunavir ethanolate, has the following chemical name: [(1S,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1­ (phenylmethyl)propyl]-carbamic acid (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester monoethanolate. Its molecular formula is C27H37N3O7S • C2H5OH and its molecular weight is 593.73.

Cobicistat: Cobicistat is adsorbed onto silicon dioxide. 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-4yl)butanoyl]amino}-1,6-diphenylhexan-2­ yl]carbamate. It has a molecular formula of C40H53N7O5S2 and a molecular weight of 776.02.

Emtricitabine: The chemical name of emtricitabine is 4-amino-5-fluoro-1-(2R-hydroxymethyl­ [1,3]-oxathiolan-5S-yl)-(1H)-pyrimidin-2-one. Emtricitabine is the (-)enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5 position. Emtricitabine has a molecular formula of C8H10FN3O3S and a molecular weight of 247.24.

Tenofovir alafenamide:The chemical name of tenofovir alafenamide fumarate drug substance is L-alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-1­ methylethoxy]methyl]phenoxyphosphinyl]-,1-methylethyl ester, (2E)-2-butenedioate (2:1). Tenofovir alafenamide fumarate has a molecular formula of C21H29O5N6P•½(C4H4O4) and a formula weight of 534.50.

Indications and usage

SYMTUZA is a four-drug combination of darunavir (DRV), a human immunodeficiency virus (HIV-1) protease inhibitor, cobicistat (COBI), a CYP3A inhibitor, and emtricitabine (FTC) and tenofovir alafenamide (TAF), both HIV-1 nucleoside analog reverse transcriptase inhibitors, and is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 40 kg:

  • who have no prior antiretroviral treatment history or
  • who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months and have no known substitutions associated with resistance to darunavir or tenofovir.

Mechanism of Action

Darunavir: Darunavir is an inhibitor of the HIV-1 protease. It selectively inhibits the cleavage of HIV-1 encoded Gag-Pol polyproteins in infected cells, thereby preventing the formation of mature virus particles.

Cobicistat: Cobicistat is a selective, mechanism-based inhibitor of CYPP450 of the CYP3A subfamily. Inhibition of CYP3A-mediated metabolism by cobicistat enhances the systemic exposure of CYP3A substrates.

Emtricitabine: Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5′-triphosphate. Emtricitabine 5′-triphosphate inhibits the activity of the HIV-1 reverse transcriptase (RT) by competing with the natural substrate deoxycytidine 5′-triphosphate and by being incorporated into nascent viral DNA, which results in chain termination. Emtricitabine 5’-triphosphate is a weak inhibitor of mammalian DNA polymerases α, β, ε, and mitochondrial DNA polymerase γ.

Tenofovir alafenamide: TAF is a phosphonamidate prodrug of tenofovir (2’-deoxyadenosine monophosphate analog). Plasma exposure to TAF allows for permeation into cells and then TAF is intracellularly converted to tenofovir through hydrolysis by cathepsin A. Tenofovir is subsequently phosphorylated by cellular kinases to the active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HIV-1 replication through incorporation into viral DNA by the HIV RT, which results in DNA chain-termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase γ and there is no evidence of toxicity to mitochondria in cell culture.

Dosage and administration

Testing: Prior to or when initiating SYMTUZA, test patients for HBV infection.

Prior to or when initiating SYMTUZA, and during treatment with SYMTUZA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus.

Recommended dosage: One tablet taken once daily with food in adults and pediatric patients, weighing at least 40 kg.

Renal Impairment: SYMTUZA is not recommended in patients with estimated creatinine clearance below 30 mL/min.

Hepatic Impairment: SYMTUZA is not recommended in patients with severe hepatic impairment.

Dosage forms and strength

Tablets: 800 mg of darunavir, 150 mg of cobicistat, 200 mg of emtricitabine, and 10 mg of tenofovir alafenamide (equivalent to 11.2 mg of tenofovir alafenamide fumarate).

Contraindications

SYMTUZA is contraindicated with the following co-administered 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 derivatives, e.g., 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 when used for treatment of pulmonary arterial hypertension
  • Sedatives/hypnotics: orally administered midazolam, triazolam

Warning and precautions

  • Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) including some fatalities can occur with SYMTUZA. Monitor liver function before and during therapy, especially in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases.
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  • Severe skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis may occur with SYMTUZA. Discontinue treatment if severe skin reaction develops.
  • Patients receiving SYMTUZA may develop new onset or exacerbations of immune reconstitution syndrome.
  • Monitor in patients with a known sulfonamide allergy.
  • Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity.
  • Patients receiving SYMTUZA may develop new onset or exacerbation of diabetes mellitus/hyperglycemia and redistribution/accumulation of body fat.
  • Patients with hemophilia may develop increase bleeding events.

Adverse reactions

The most common adverse reactions (all grades, incidence greater than or equal to 2%) were diarrhea, rash, nausea, fatigue, headache, abdominal discomfort, and flatulence.

To report SUSPECTED ADVERSE REACTIONS, contact Janssen Products, LP at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA1088 or www.fda.gov/medwatch.

Drug interactions

Co-administration of SYMTUZA with other drugs can alter the concentration of other drugs and other drugs may alter the concentrations of SYMTUZA components. Consult the full prescribing information prior to and during treatment for potential drug interactions.

Use in specific populations

Pregnancy: SYMTUZA is not recommended for use during pregnancy because of substantially lower exposures of darunavir and cobicistat during pregnancy.

SYMTUZA should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with SYMTUZA.

Lactation: The Centers for Disease Control and Prevention recommend that HIV-infected mothers in the United States must not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.

Based on published data, emtricitabine has been shown to be present in human breast milk. There are no data on the presence of darunavir, cobicistat, or TAF in human milk, the effects on the breastfed infant, or the effects on milk production.

Pediatric Use: The safety and effectiveness of SYMTUZA for the treatment of HIV-1 infection in pediatric patients weighing at least 40 kg was established through studies with components of SYMTUZA.

The safety and effectiveness of SYMTUZA have not been established in pediatric patients weighing less than 40 kg.

Darunavir, a component of SYMTUZA is not recommended in pediatric patients below 3 years of age because of toxicity and mortality observed in juvenile rats dosed with darunavir.

Geriatric Use: Clinical trials of SYMTUZA included 35 subjects aged above 65 years of which 26 received SYMTUZA. No differences in safety or efficacy have been observed between elderly subjects and those aged 65 years or less. In general, caution should be exercised in the administration and monitoring of SYMTUZA in elderly patients, reflecting the greater frequency of decreased hepatic function and of concomitant disease or other drug therapy

Renal Impairment: SYMTUZA is not recommended in patients with severe renal impairment (creatinine clearance below 30 mL per minute). No dosage adjustment of SYMTUZA is required in patients with creatinine clearance greater than or equal to 30 mL per minute.

Hepatic Impairment: No dosage adjustment of SYMTUZA is required in patients with mild (Child Pugh Class A) or moderate (Child Pugh Class B) hepatic impairment. SYMTUZA has not been studied in patients with severe hepatic impairment (Child Pugh Class C) and there are only limited data regarding the use of SYMTUZA components in this population. Therefore, SYMTUZA is not recommended for use in patients with severe hepatic impairment.

Overdosage

Human experience of acute overdose with SYMTUZA is limited. There is no specific antidote for overdose with SYMTUZA. Treatment of overdose with SYMTUZA consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.

Since darunavir and cobicistat are highly bound to plasma proteins, it is unlikely that they will be significantly removed by hemodialysis or peritoneal dialysis. Hemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min). Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. It is not known whether emtricitabine or tenofovir can be removed by peritoneal dialysis.

Storage and handling
  • Store at 20°C-25°C (between 68°F-77°F); with excursions permitted to 15°C-30°C (59°F86°F).
  • Dispense only in the original container. Keep container tightly closed with desiccant inside to protect from moisture.

Keep SYMTUZA out of reach of children.

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