SYMFI LO
Clinical safety rating: caution
Comprehensive clinical and safety monograph for SYMFI LO (SYMFI LO).
SYMFI LO is a fixed-dose combination of efavirenz, lamivudine, and tenofovir disoproxil fumarate. Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that binds reversibly to the HIV-1 reverse transcriptase enzyme, causing a conformational change that inhibits RNA- and DNA-dependent DNA polymerase activities. Lamivudine and tenofovir disoproxil fumarate are nucleoside analogue reverse transcriptase inhibitors (NRTIs); they are phosphorylated to active metabolites that compete with natural substrates and incorporate into viral DNA, causing chain termination.
| Metabolism | Efavirenz is primarily metabolized by the cytochrome P450 enzyme system (CYP2B6 and CYP3A4/5). Lamivudine is eliminated renally as unchanged drug and undergoes limited hepatic metabolism (5-10%). Tenofovir disoproxil fumarate is a prodrug that is converted to tenofovir, which is eliminated renally by glomerular filtration and active tubular secretion. |
| Excretion | Efavirenz: ~34% renal (1% unchanged, rest as metabolites), ~61% fecal (16% unchanged). Emtricitabine: ~86% renal (70% unchanged), ~14% fecal. Tenofovir disoproxil fumarate: ~70-80% renal as unchanged tenofovir via glomerular filtration and active tubular secretion. |
| Half-life | Efavirenz: 40-55 hours (single dose), 52-76 hours (multiple doses); clinically permits once-daily dosing. Emtricitabine: 10 hours; supports once-daily dosing. Tenofovir disoproxil fumarate: 17 hours (tenofovir intracellular half-life ~60 hours); long intracellular persistence. |
| Protein binding | Efavirenz: 99.5-99.75% bound, primarily to albumin. Emtricitabine: <4% bound. Tenofovir: <7% bound to plasma proteins. |
| Volume of Distribution | Efavirenz: 252 L (3.6 L/kg for 70 kg); extensive tissue distribution. Emtricitabine: 1.4 L/kg; distributes into total body water. Tenofovir disoproxil fumarate: 1.3 L/kg; distributes into extravascular space. |
| Bioavailability | Oral: Efavirenz 40-45% (increased with high-fat meal); Emtricitabine 93%; Tenofovir disoproxil fumarate 25% (fasted), 39% (with high-fat meal). |
| Onset of Action | Oral: Antiviral effect begins within 2-4 hours after first dose; maximal suppression typically achieved within 2-4 weeks. |
| Duration of Action | Oral: Drug levels remain above therapeutic threshold for 24 hours with once-daily dosing; full virologic suppression maintained with adherence. Missed doses reduce duration of protection; re-dosing within 12 hours of scheduled time recommended. |
One tablet (efavirenz 600 mg/lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg) orally once daily on an empty stomach, preferably at bedtime.
| Dosage form | TABLET |
| Renal impairment | Not recommended if creatinine clearance (CrCl) < 50 mL/min. If CrCl 30-49 mL/min, use individual components with dose adjustments: tenofovir DF 300 mg every 48 hours, lamivudine 150 mg once daily, efavirenz 600 mg once daily. If CrCl < 30 mL/min, do not use; consider alternative regimen. |
| Liver impairment | Contraindicated in Child-Pugh class C. For Child-Pugh class A or B, use with caution; no specific dose adjustment recommended, but monitor hepatic function. Efavirenz is not recommended for patients with moderate to severe hepatic impairment. |
| Pediatric use | Not recommended for pediatric patients < 12 years of age or < 40 kg. For adolescents ≥ 12 years and ≥ 40 kg, same as adult dosing: one tablet once daily. |
| Geriatric use | No specific dose adjustment; monitor renal function (CrCl) and bone mineral density due to increased risk of renal impairment and osteoporosis in elderly. Choose regimen based on renal function. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for SYMFI LO (SYMFI LO).
| Breastfeeding | Breastfeeding is not recommended for HIV-positive mothers to avoid postnatal HIV transmission. If required, limited data suggest lamivudine and tenofovir are excreted into breast milk; efavirenz appears in low levels. M/P ratio not established. Weigh benefits of breastfeeding against risk of HIV transmission and potential infant toxicity. |
| Teratogenic Risk | SYMFI LO (efavirenz/lamivudine/tenofovir disoproxil fumarate) is contraindicated in the first trimester due to efavirenz's association with neural tube defects (risk of fetal CNS malformations). In the second and third trimesters, use only if benefit outweighs risk; lamivudine and tenofovir have not demonstrated significant teratogenicity. Limited data exist for the combination. |
■ 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 co-infected with hepatitis B virus (HBV) and HIV-1 and have discontinued lamivudine or tenofovir disoproxil fumarate (components of SYMFI LO). Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue SYMFI LO.
| Serious Effects |
["Hypersensitivity to any component of the product","Coadministration with elbasvir/grazoprevir (due to significant decrease in grazoprevir concentrations and potential for loss of virologic response)","Coadministration with certain drugs that are highly dependent on CYP2B6 or CYP3A4 for clearance and for which elevated plasma concentrations are associated with serious adverse events (e.g., cisapride, ergot derivatives, midazolam, triazolam, pimozide, St. John's wort)"]
| Precautions | ["Hepatotoxicity: Hepatic adverse events, including life-threatening hepatotoxicity, have been reported with efavirenz. Monitor liver enzymes before and during therapy.","Psychiatric symptoms: Serious psychiatric adverse events including severe depression, suicidal ideation, and psychosis have been reported with efavirenz.","Convulsions: Seizures have been reported, primarily in patients with history of seizures.","Renal impairment: Tenofovir disoproxil fumarate can cause renal impairment, including acute renal failure and Fanconi syndrome. Assess creatinine clearance before initiation and monitor during therapy.","Lactic acidosis/severe hepatomegaly with steatosis: Reported with NRTIs including lamivudine and tenofovir.","Immune reconstitution syndrome: Inflammatory response to indolent or residual opportunistic infections may occur during initial treatment.","Bone effects: Decreases in bone mineral density observed with tenofovir disoproxil fumarate.","Co-infection with HBV: Monitor for hepatitis B exacerbation upon discontinuation (see black box warning)."] |
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| Fetal Monitoring | Monitor HIV viral load, CD4 count, liver function tests, serum creatinine, and renal function at baseline and throughout pregnancy. Perform fetal ultrasound for neural tube defects if exposed in first trimester. Assess infant for HIV status postnatally. |
| Fertility Effects | No definitive evidence of impaired fertility in humans. Efavirenz may cause menstrual irregularities; lamivudine and tenofovir have not demonstrated adverse fertility effects in animal studies. |