SYMTUZA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for SYMTUZA (SYMTUZA).
SYMTUZA is a fixed-dose combination of darunavir (a HIV-1 protease inhibitor), cobicistat (a CYP3A inhibitor), emtricitabine (a nucleoside reverse transcriptase inhibitor), and tenofovir alafenamide (a nucleotide reverse transcriptase inhibitor). Darunavir inhibits HIV-1 protease, preventing cleavage of viral polyproteins and resulting in immature, non-infectious virus. Emtricitabine and tenofovir alafenamide inhibit HIV reverse transcriptase by competing with natural substrates and causing DNA chain termination. Cobicistat inhibits CYP3A, boosting darunavir exposure.
| Metabolism | Darunavir is primarily metabolized by CYP3A. Cobicistat is metabolized by CYP3A and to a minor extent by CYP2D6. Emtricitabine is not significantly metabolized. Tenofovir alafenamide is metabolized by cathepsin A in PBMCs and by CES1 in hepatocytes; it is a substrate of P-gp and BCRP. |
| Excretion | Darunavir: ~80% feces (mostly metabolites), ~14% urine (unchanged 1.5%). Cobicistat: ~86% feces, ~8% urine. Emtricitabine: ~86% urine (unchanged), ~14% feces. Tenofovir alafenamide: ~31% urine, ~47% feces (as tenofovir). |
| Half-life | Darunavir: 15 hours (when boosted with cobicistat). Cobicistat: 3-4 hours. Emtricitabine: 10 hours. Tenofovir alafenamide: 0.5 hours (active metabolite tenofovir diphosphate intracellular half-life >60 hours). |
| Protein binding | Darunavir: ~95% (alpha-1-acid glycoprotein). Cobicistat: 97-98% (serum albumin). Emtricitabine: <4%. Tenofovir alafenamide: ~80%. |
| Volume of Distribution | Darunavir: 1.5 L/kg (extensive tissue penetration). Cobicistat: 1.7 L/kg. Emtricitabine: 1.4 L/kg. Tenofovir alafenamide: 0.8 L/kg (high distribution to lymphoid tissues). |
| Bioavailability | Oral: Darunavir ~37% (increased with food; absolute bioavailability not determined). Cobicistat: ~90%. Emtricitabine: 93%. Tenofovir alafenamide: ~40% (food increases exposure). |
| Onset of Action | Oral: Antiviral effect begins within hours of first dose; maximal virologic suppression achieved within 2-4 weeks. |
| Duration of Action | Oral: Dosing every 24 hours maintains therapeutic concentrations due to long intracellular half-life of tenofovir diphosphate and once-daily regimen; missed dose should be taken as soon as remembered if within 12 hours. |
One tablet (darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg) orally once daily with food.
| Dosage form | TABLET |
| Renal impairment | Not recommended for CrCl <30 mL/min. No dose adjustment for CrCl ≥30 mL/min. For CrCl 30-50 mL/min, monitor renal function. |
| Liver impairment | Contraindicated in severe hepatic impairment (Child-Pugh C). Not recommended for moderate impairment (Child-Pugh B). No adjustment for mild impairment (Child-Pugh A). |
| Pediatric use | Approved for body weight ≥40 kg: one tablet orally once daily with food. For weight <40 kg, not recommended. |
| Geriatric use | No specific dose adjustment; monitor renal function and bone mineral density due to increased risk of age-related comorbidities. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for SYMTUZA (SYMTUZA).
| Breastfeeding | Breastfeeding is not recommended due to the potential for HIV transmission and adverse effects in the infant. Emtricitabine and tenofovir are excreted in human milk; the M/P ratio for tenofovir is approximately 1.2. Darunavir and cobicistat concentrations in breast milk are unknown. |
| Teratogenic Risk | SYMTUZA (darunavir/cobicistat/emtricitabine/tenofovir alafenamide) is classified as Pregnancy Category B for the individual components. There are no adequate and well-controlled studies in pregnant women. Animal studies have not shown evidence of teratogenicity. Use during pregnancy only if clearly needed. |
■ FDA Black Box Warning
WARNING: POST-TREATMENT ACUTE EXACERBATION OF HEPATITIS B. 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 alafenamide is a prodrug of tenofovir). Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue SYMTUZA and are coinfected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
| Serious Effects |
["SYMTUZA is contraindicated in patients with previous hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, toxic skin eruption) to darunavir, cobicistat, emtricitabine, tenofovir alafenamide, or any of the components.","Co-administration with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (e.g., alfuzosin, amiodarone, quinidine, dihydroergotamine, ergotamine, methylergonovine, cisapride, pimozide, oral midazolam, triazolam, lovastatin, simvastatin, sildenafil for pulmonary arterial hypertension, St. John's wort).","Co-administration with rifampin."]
| Precautions | ["Severe acute exacerbation of hepatitis B in patients coinfected with HIV-1 and HBV (see black box warning)","Hepatotoxicity: hepatic adverse events including elevations of liver enzymes, hepatitis, and hepatic injury (including fatal cases) have been reported. Monitoring of liver function is recommended.","Risk of adverse reactions or loss of virologic response due to drug interactions: use with certain drugs may result in loss of therapeutic effect or adverse events.","Renal impairment: tenofovir alafenamide is not recommended in patients with severe renal impairment (CrCl <30 mL/min).","Decreases in bone mineral density have been observed with tenofovir alafenamide.","Immune reconstitution syndrome has been reported."] |
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| Fetal Monitoring | Monitor HIV RNA viral load and CD4+ cell count throughout pregnancy. Assess renal function and liver enzymes. Monitor for adverse effects such as nausea, diarrhea, and headache. Consider ultrasound for fetal growth if prolonged use. |
| Fertility Effects | No significant adverse effects on fertility have been reported in animal studies or human data. HIV itself may affect fertility, but effective viral suppression improves fertility outcomes. |