Boxed WARNING and
Important Safety Information

The approval of SYMFI LO was supported by two clinical trials: Study 903 in 2004, and the ENCORE1 trial in 2014. Study 903 tested the efficacy of tenofovir disproxil fumarate (TDF, 300 mg), lamivudine (3TC, 300 mg), and efavirenz (EFV, 600 mg) together to treat an HIV-1 infection. The ENCORE1 trial demonstrated that a reduced dose of 400 mg efavirenz is non-inferior to the standard dose of 600 mg, when combined with tenofovir and emtricitabine during 48 weeks in ART-naive adults with HIV-1 infection.

SYMFI LO is a single-tablet regimen to incorporate a 400 mg, instead of a 600 mg, dose of efavirenz.

ENCORE 1 study

Study design

Patients

630 antiretroviral naïve HIV-1 patients from 13 countries

Study sites

38 sites in the Americas (Argentina, Chile, Mexico), Europe (Germany, UK), Asia/Oceania

(Australia, Israel, Hong Kong, Malaysia, Singapore, Thailand), and Africa (Nigeria, South Africa)

Length

48 weeks

Treatment arms

TDF + FTC + EFV (600 mg)

TDF + FTC + EFV (400 mg)

Subjects

  • 68% male, 32% female (mean age of 36 years)
  • Randomization was stratified by the clinical sites and the screening visit plasma HIV-1 RNA level, either < 100,000 copies/mL or ≥ 100,000 copies/mL

Note: It is important to note that the ENCORE 1 clinical study was designed to examine the differences in a drug regimen that includes 600 mg or a lower dose of efavirenz which is 400 mg, but it did not specifically study the SYMFI LO formulation, which includes a combination of tenofovir disoproxil fumarate, lamivudine (3TC) and 400 mg of efavirenz.

Study results

The ENCORE 1 study demonstrated that a 400 mg daily dose of EFV is non-inferior to 600 mg as measured by percentage of patients achieving viral suppression (defined as less than 50 copies/ml) in treatment naïve adults.

FTC + TDF +
EFV 400 mg
(N=321)
FTC + TDF +
EFV 600 mg
(N=309)
% Subjects achieved confirmed HIV-1 RNA < 50 copies/mL at Week 48 86% 84%
Mean increase at Week 48 from baseline CD4 count (cells/mm3) +183
Mean CD4 count increase
+158
Mean CD4 count increase

ENCORE1 did not test SYMFI LO itself. SYMFI LO is a combination of EFV, 3TC (Lamivudine), and TDF.

ENCORE1 compared 2 regimens of EFV, FTC, and TDF with varying levels of EFV.

Change in HIV-1 RNA viral load from baseline to week 48: Results from the ENCORE1 study

Mean change in HIV-1 RNA viral load from baseline to week 48 (log10 copies per mL)

studyresult tab2 graph

 

Selected Adverse Reactionsa (Grades 2-4) reported in ≥ 2% in either treatment group in the ENCORE1 study through Week 48

TDF: Tenofovir disoproxil fumarate; FTC: Emtricitabine; EFV: Efavirenz

  • 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.

Note: Your individual results may vary.

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SYMFI LO IMPORTANT SAFETY INFORMATION

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WARNING: POST TREATMENT ACUTE EXACERBATIONS OF HEPATITIS B
Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine or tenofovir disoproxil fumarate, two components of SYMFI LO. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment [see Warnings and Precautions (5.1)].

Important Safety Information

SYMFI LO is contraindicated:

  • in patients with a previous hypersensitivity reaction (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components contained in the formulation.
  • when coadministered with elbasvir and grazoprevir.

All patients with HIV-1 should be tested for the presence of chronic hepatitis B virus (HBV) before initiating antiretroviral therapy.
Discontinuation of anti-HBV therapy, including lamivudine (3TC) and tenofovir disoproxil fumarate (TDF), may be associated with severe acute exacerbations of hepatitis. Patients infected with HBV who discontinue SYMFI LO should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of anti-hepatitis B therapy may be warranted. See the full prescribing information for Important Differences Among Lamivudine-Containing Products.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs and other antiretrovirals. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. Treatment should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

The concomitant use of SYMFI LO and other drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effect of SYMFI LO and possible development of resistance or possible clinically significant adverse reactions from greater exposures of concomitant drugs. See Table 5 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations.

TDF, a component of SYMFI LO is principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of TDF.

Prior to initiation and during use of SYMFI LO, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients.

SYMFI LO should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs (NSAIDS)).

Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in patients at risk of renal dysfunction.

Serious psychiatric adverse experiences have been reported in patients treated with efavirenz (EFV), a component of SYMFI LO. In controlled trials in patients treated with regimens containing EFV the following serious psychiatric events occurred: severe depression, suicidal ideation, nonfatal suicide attempts, aggressive behavior, paranoid reactions, and manic reactions. When psychiatric symptoms similar to those noted above were combined and evaluated as a group in a multifactorial analysis of data from a study using EFV 600 mg, treatment with EFV was associated with an increase in the occurrence of these selected psychiatric symptoms. There have also been occasional post marketing reports of serious psychiatric symptoms. See full prescribing information for other factors associated with an increase in the occurrence of psychiatric symptoms.

Patients receiving EFV, a component of SYMFI LO, in controlled trials reported central nervous system symptoms. These symptoms included, but were not limited to, dizziness, insomnia, impaired concentration, somnolence, abnormal dreams, and hallucinations. These symptoms were severe in 2% of patients and 2.1% of patients discontinued therapy as a result. Patients should be informed that these common symptoms usually begin during the first or second day of therapy and were likely to improve with continued therapy and were not predictive of subsequent onset of the less frequent psychiatric symptoms.

Late-onset neurotoxicity, including ataxia and encephalopathy (impaired consciousness, confusion, psychomotor slowing, psychosis, delirium), may occur months to years after beginning efavirenz therapy. Some events of late-onset neurotoxicity have occurred in patients with CYP2B6 genetic polymorphisms which are associated with increased efavirenz levels. Patients presenting with signs and symptoms of serious neurologic adverse experiences should be evaluated promptly to assess the possibility that these events may be related to efavirenz use, and whether discontinuation of SYMFI LO is warranted.

EFV, a component of SYMFI LO, may cause fetal harm when administered during the first trimester to a pregnant woman. Females of reproductive potential who are receiving EFV should avoid pregnancy.

In controlled clinical trials, patients treated with 600 mg EFV experienced new-onset skin rash associated with blistering, moist desquamation, or ulceration.

EFV should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement, or fever. EFV can generally be reinitiated in patients interrupting therapy because of rash.

EFV, a component of SYMFI LO, is not recommended for patients with moderate or severe hepatic impairment. Careful monitoring is recommended for patients with mild hepatic impairment receiving EFV.

Monitoring of liver enzymes before and during treatment is recommended for all patients. Consider discontinuing SYMFI LO in patients with persistent elevations of serum transaminases to greater than five times the upper limit of the normal range. 

Discontinue SYMFI LO if elevation of serum transaminases is accompanied by clinical signs or symptoms of hepatitis or hepatic decompensation.

In pediatric patients with a history of prior antiretroviral nucleoside exposure, a history of pancreatitis, or other significant risk factors for the development of pancreatitis, 3TC, a component of SYMFI LO, should be used with caution. Treatment with SYMFI LO should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur.

Convulsions have been observed in patients receiving EFV, generally in the presence of known medical history of seizures. Caution should be taken in any patient with a history of seizures. Patients who are receiving concomitant anticonvulsant medications primarily metabolized by the liver, such as phenytoin and phenobarbital, may require periodic monitoring of plasma levels.

Treatment with EFV has resulted in increases in the concentration of total cholesterol and triglycerides. Cholesterol and triglyceride testing should be performed before initiating EFV therapy and at periodic intervals during therapy.

In clinical trials in HIV-1 infected adults, TDF was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving TDF. The effects of TDF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk in adults and pediatric patients 2 years and older are unknown.

Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of TDF.

Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barre syndrome and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution in patients treated with combination antiretroviral therapy, including EFV, 3TC, and TDF.

In HIV-infected patients, redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving combination antiretroviral therapy.

QTc prolongation has been observed with the use of EFV.

Most common adverse reactions (> 5% with SYMFI LO components) are rash and dizziness.

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Indication

SYMFI LO® (efavirenz, lamivudine and tenofovir disoproxil fumarate) is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adult and pediatric patients weighing at least 35 kg.