FDA approved SYMFI LO Tablets which is a fixed dose combination product containing 400 mg efavirenz, 300 mg lamivudine and 300 mg tenofovir disoproxil fumarate (equivalent to 245 mg of tenofovir disoproxil) and is indicated as a complete regimen for the treatment of HIV-1 in adult and pediatric patients weighing at least 35 kg. Highlights from the product labeling are as follows:
DOSAGE AND ADMINISTRATION
SYMFI LO is contraindicated in patients with previous hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product and is contraindicated with elbasvir/grazoprevir coadministration
The WARNINGS AND PRECAUTIONS include:
ENCORE1 Study - Adverse Reactions: The most common adverse reactions seen in a double-blind comparative controlled study in which 630 treatment-naïve subjects received EFV 400 mg (N = 321) or EFV 600 mg (N = 309) in combination with fixed-dose emtricitabine (FTC)/TDF for 48 weeks were mild to moderate gastrointestinal events, dizziness, abnormal dreams, and rash. Selected clinical adverse reactions of moderate or severe intensity reported in ≥ 2% of treatment-naive patients receiving combination therapy including EFV 400 mg and EFV 600 mg are presented in below.
Selected Adverse Reactionsa (Grades 2-4) Reported in ≥ 2% in Either Treatment Group in the ENCORE1 Study through Week 48
a Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug.
b Rash events include dermatitis allergic, drug hypersensitivity, pruritus generalized, eosinophilic pustular folliculitis, rash, rash erythematous, rash generalized, rash macular, rash maculopapular, rash morbilliform, rash papular, rash pruritic, rash vesicular, and urticaria.
In ENCORE1 study, a summary of Grade 3 and 4 laboratory abnormalities is provided below
Grades 3-4 Laboratory Abnormalities in ≥ 2% in Either Treatment Group Through Week 48
CLINICAL STUDIES
Treatment-Naïve Adult Patients: The efficacy of EFV 400 mg, 3TC 300 mg, and TDF 300 mg
in the treatment of HIV-1 infection in adults with no antiretroviral treatment history was established in trials of:
EFV 600 mg in 630 antiretroviral-naïve adult subjects. Subjects were randomized 1:1 to receive EFV 400 mg in combination with TDF 300 mg plus FTC 200 mg all given once daily or EFV 600 mg in combination with TDF 300 mg/FTC 200 mg given once daily. The randomization was stratified by the clinical sites and the screening visit plasma HIV RNA level, either < 100,000 copies/mL or ≥ 100,000 copies/mL.
Subjects had a mean age of 36 years (range 18 to 69), 68% were male, 37% were of African heritage, 33% were of Asian ethnicity, 17% were Hispanic and 13% were Caucasian.
The mean baseline CD4+ cell count was 273 cells/mm3 (range 38 to 679). Median baseline viral load was 56,469 copies/mL (range 162 to 10,000,000). Thirty-four percent of subjects had baseline viral load of ≥ 100,000 copies/mL.
Treatment outcomes through Week 48 are presented in below.
Virologic Outcomes of Randomized Treatment in Trial ENCORE 1 in Treatment-Naïve Subjects at Week 48
aSubjects achieved confirmed HIV-1 RNA < 50 copies/mL at Week 48.
bIncludes confirmed viral rebound and failure to achieve confirmed < 50 copies/mL through Week 48
cIncludes discontinued due to Adverse Event, lost to follow-up, subject’s withdrawal, noncompliance, protocol violation and other reasons.
Achievement of plasma HIV-1 RNA concentrations of less than 50 copies/mL at Week 48 was
similar between the two treatment groups for the population stratified at baseline on the basis of HIV-1 RNA concentration (< or ≥ 100,000 copies/mL). The mean increase at Week 48 from baseline in CD4+ cell count was 183 cells/mm3 for the EFV 400 mg arm and 158 cells/mm3 for the EFV 600 mg arm. Through 48 weeks, 11 subjects in the EFV 400 mg group and 5 subjects in the EFV 600 mg group experienced a new CDC Class C event.
DOSAGE AND ADMINISTRATION
- Testing: Prior to initiation and during treatment with SYMFI LO, patients should be tested for hepatitis B virus infection, and estimated creatinine clearance, urine glucose, and urine protein should be obtained.
- Recommended dose: One tablet taken orally once daily on an empty stomach, preferably at bedtime. Dosing at bedtime may improve the tolerability of nervous system symptoms
- Renal Impairment: Not recommended in patients with CrCL less than 50 mL/min or patients with end-stage renal disease requiring hemodialysis.
- Hepatic Impairment: Not recommended for patients with moderate or severe hepatic impairment. Use caution in patients with mild hepatic impairment.
SYMFI LO is contraindicated in patients with previous hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product and is contraindicated with elbasvir/grazoprevir coadministration
The WARNINGS AND PRECAUTIONS include:
- Lactic Acidosis/Severe Hepatomegaly with Steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity.
- New Onset or Worsening Renal Impairment: Can include acute renal failure and Fanconi syndrome. Assess estimated creatinine clearance before initiating treatment with tenofovir disoproxil fumarate, a component of SYMFI LO. In patients at risk for renal dysfunction, assess estimated creatinine clearance, serum phosphorus, urine glucose and urine protein before initiating treatment with tenofovir and periodically during treatment. Avoid administering SYMFI LO with concurrent or recent use of nephrotoxic drugs.
- Serious Psychiatric Symptoms: Immediate medical evaluation is recommended for serious psychiatric symptoms such as severe depression or suicidal ideation.
- In the ENCORE1 (Evaluation of Novel Concepts in Optimization of antiRetroviral Efficacy) study, at Week 48 the frequency (regardless of causality) of the most common (occurring in > 1% patients) psychiatric events among patients who received EFV 400 mg (N = 321) or EFV 600 mg (N = 309) regimens, respectively, were: abnormal dreams (8.7%, 11.3%), insomnia (6.2%, 6.5%), somnolence (3.1%, 3.9%), depression (3.1%, 1.6%), nightmare (1.9%, 2.6%), sleep disorder (2.2%, 1.3%), and anxiety (1.2%, 1.3%).
- Nervous System Symptoms (NSS): NSS are frequent, usually begin 1 to 2 days after initiating therapy and resolve in 2 to 4 weeks. Dosing at bedtime may improve tolerability. NSS are not predictive of onset of psychiatric symptoms.
- In the ENCORE1 study, at Week 48, 40% of EFV 400 mg recipients and 48% of EFV 600 mg recipients reported central nervous system disorders. The most common symptoms (> 10%) were dizziness (27% vs. 35%) and headache (11% vs. 11%).
- Embryo-Fetal Toxicity: Advise females of reproductive potential who are receiving efavirenz to avoid pregnancy.
- Rash: Rash usually begins within 1 to 2 weeks after initiating therapy and resolves within 4 weeks. Discontinue if severe rash develops.
- In the ENCORE1 study at Week 48, different types of rash (such as rash, rash papular, rash maculopapular and rash pruritic) occurred in 32% of EFV 600 mg recipients and 26% of EFV 400 mg recipients. Grade 3-4 rash was reported in 3% of EFV 600 mg recipients and 1% of EFV 400 mg recipients. The discontinuation rate for rash in the ENCORE1 study was 3% of EFV 600 mg recipients and 1% of EFV 400 mg recipients.
- Hepatotoxicity: Monitor liver function tests before and during treatment in patients with underlying hepatic disease, including hepatitis B or C coinfection, marked transaminase elevations, or who are taking medications associated with liver toxicity. Among reported cases of hepatic failure, a few occurred in patients with no pre-existing hepatic disease.
- Hepatic decompensation, some fatal, has occurred in HIV-1/HCV co- infected patients receiving combination antiretroviral therapy and interferon and ribavirin-based regimens. Monitor for treatment-associated toxicities. Discontinue SYMFI LO, as medically appropriate, and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both.
- Pancreatitis: Use with caution in pediatric patients with a history of pancreatitis or other significant risk factors for pancreatitis. Discontinue SYMFI LO as clinically appropriate.
- Convulsions: Use caution in patients with a history of seizures.
- Lipids: Total cholesterol and triglyceride elevations. Monitor before therapy and periodically thereafter.
- Decreases in Bone Mineral Density (BMD): Observed in HIV-infected patients. Consider assessment of BMD in patients with a history of pathologic fracture or other risk factors for osteoporosis or bone loss.
- Immune Reconstitution Syndrome: Observed in HIV-infected patients.
- May necessitate further evaluation and treatment.
- Redistribution/Accumulation of Body Fat: Observed in HIV-infected
ENCORE1 Study - Adverse Reactions: The most common adverse reactions seen in a double-blind comparative controlled study in which 630 treatment-naïve subjects received EFV 400 mg (N = 321) or EFV 600 mg (N = 309) in combination with fixed-dose emtricitabine (FTC)/TDF for 48 weeks were mild to moderate gastrointestinal events, dizziness, abnormal dreams, and rash. Selected clinical adverse reactions of moderate or severe intensity reported in ≥ 2% of treatment-naive patients receiving combination therapy including EFV 400 mg and EFV 600 mg are presented in below.
Selected Adverse Reactionsa (Grades 2-4) Reported in ≥ 2% in Either Treatment Group in the ENCORE1 Study through Week 48
| EFV 400 mg + FTC/TDF | EFV 600 mg + FTC/TDF | |
| N = 321 | N = 309 | |
| Rash eventb | 9% | 13% |
| Dizziness | 6% | 9% |
| Insomnia | 3% | 4% |
| Abnormal dreams | 2% | 2% |
| Headache | 1% | 3% |
| Diarrhea | 2% | 3% |
| Vomiting | 1% | 2% |
| Pyrexia | 2% | 1% |
| Upper respiratory tract infection | 3% | 1% |
| Nasopharyngitis | 3% | 2% |
| Herpes zoster | 3% | 1% |
| Gastroenteritis | 2% | 2% |
a Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug.
b Rash events include dermatitis allergic, drug hypersensitivity, pruritus generalized, eosinophilic pustular folliculitis, rash, rash erythematous, rash generalized, rash macular, rash maculopapular, rash morbilliform, rash papular, rash pruritic, rash vesicular, and urticaria.
In ENCORE1 study, a summary of Grade 3 and 4 laboratory abnormalities is provided below
Grades 3-4 Laboratory Abnormalities in ≥ 2% in Either Treatment Group Through Week 48
| Laboratory Parameter | EFV 400 mg + FTC + TDF | EFV 600 mg + FTC + TDF |
| N = 321 | N = 309 | |
| ALT | 5% | 3% |
| AST | 2% | 2% |
| Total bilirubin | 0.3% | 3% |
| Cholesterol | 2% | 5% |
| Neutrophils | 2% | 3% |
| Phosphorus | 2% | 3% |
CLINICAL STUDIES
Treatment-Naïve Adult Patients: The efficacy of EFV 400 mg, 3TC 300 mg, and TDF 300 mg
in the treatment of HIV-1 infection in adults with no antiretroviral treatment history was established in trials of:
- Trial 903 which evaluated the efficacy of a three-drug regimen including EFV 600 mg, 3TC 300 mg and TDF 300 mg
- ENCORE1, which evaluated the comparability of 400 mg of EFV in a triple drug regimen to a 600 mg dose of EFV in a triple drug regimen.
EFV 600 mg in 630 antiretroviral-naïve adult subjects. Subjects were randomized 1:1 to receive EFV 400 mg in combination with TDF 300 mg plus FTC 200 mg all given once daily or EFV 600 mg in combination with TDF 300 mg/FTC 200 mg given once daily. The randomization was stratified by the clinical sites and the screening visit plasma HIV RNA level, either < 100,000 copies/mL or ≥ 100,000 copies/mL.
Subjects had a mean age of 36 years (range 18 to 69), 68% were male, 37% were of African heritage, 33% were of Asian ethnicity, 17% were Hispanic and 13% were Caucasian.
The mean baseline CD4+ cell count was 273 cells/mm3 (range 38 to 679). Median baseline viral load was 56,469 copies/mL (range 162 to 10,000,000). Thirty-four percent of subjects had baseline viral load of ≥ 100,000 copies/mL.
Treatment outcomes through Week 48 are presented in below.
Virologic Outcomes of Randomized Treatment in Trial ENCORE 1 in Treatment-Naïve Subjects at Week 48
| At Week 48 | ||
Outcomes (< 50 copies/mL) | EFV400 mg +FTC+ TDF (N = 321) | EFV600 mg +FTC + TDF (N = 309) |
| Respondera HIV-1 RNA < 50 copies/mL | 86% | 84% |
| Virologic failureb HIV-1 RNA ≥ 50 copies/mL | 11% | 11% |
| Rebound | 9% | 8% |
| Never suppressed | 2% | 3% |
| Death | 1% | 1% |
| Discontinued for other reasonsc | 2% | 4% |
bIncludes confirmed viral rebound and failure to achieve confirmed < 50 copies/mL through Week 48
cIncludes discontinued due to Adverse Event, lost to follow-up, subject’s withdrawal, noncompliance, protocol violation and other reasons.
Achievement of plasma HIV-1 RNA concentrations of less than 50 copies/mL at Week 48 was
similar between the two treatment groups for the population stratified at baseline on the basis of HIV-1 RNA concentration (< or ≥ 100,000 copies/mL). The mean increase at Week 48 from baseline in CD4+ cell count was 183 cells/mm3 for the EFV 400 mg arm and 158 cells/mm3 for the EFV 600 mg arm. Through 48 weeks, 11 subjects in the EFV 400 mg group and 5 subjects in the EFV 600 mg group experienced a new CDC Class C event.
Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration
Food and Drug Administration
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration
Division of Antiviral Products
Food and Drug Administration
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