Symfi Lo

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 [see Warnings and Precautions (5.8)]. • when coadministered with elbasvir and grazoprevir [see Warnings and Precautions (5.3) and Drug Interactions (7.5)].

Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs and other antiretrovirals. 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).

Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV

Posttreatment Exacerbations of Hepatitis

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 3TC and 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.

Important Differences Among Lamivudine-Containing Products

Symfi Lo tablets contain a higher dose of the same active ingredient, 3TC, than EPIVIR-HBV® tablets. EPIVIR-HBV was developed for patients with chronic hepatitis B. The formulation and dosage of 3TC in EPIVIR-HBV are not appropriate for patients co-infected with HIV-1 and HBV. Safety and efficacy of 3TC have not been established for treatment of chronic hepatitis B in patients co-infected with HIV-1 and HBV.

If treatment with EPIVIR-HBV, TDF, or a tenofovir alafenamide (TAF)-containing product is prescribed for chronic hepatitis B for a patient with unrecognized or untreated HIV-1 infection, rapid emergence of HIV-1 resistance is likely to result because of the subtherapeutic dose and the inappropriateness of monotherapy HIV-1 treatment.

Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions

The concomitant use of Symfi Lo and other drugs may result in known or potentially significant drug interactions, some of which may lead to [see Contraindications (4) and Drug Interactions (7.5)]:

• Loss of therapeutic effect of Symfi Lo and possible development of resistance. • 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 [see Drug Interactions (7.5)]. Consider the potential for drug interactions prior to and during Symfi Lo therapy; review concomitant medications during Symfi Lo therapy; and monitor for the adverse reactions associated with the concomitant drugs.

New Onset or Worsening Renal Impairment

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 [see Adverse Reactions (6.2)].

It is recommended that estimated creatinine clearance be assessed in all patients prior to initiating therapy and as clinically appropriate during therapy with TDF. In patients at risk of renal dysfunction, it is recommended that estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein be assessed prior to initiation of tenofovir disoproxil fumarate, and periodically during TDF therapy.

Avoid Symfi Lo with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs)) [see Drug Interactions (7.3)]. Cases of acute renal failure after initiation of high dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on TDF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction.

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 at-risk patients.

Psychiatric Symptoms

Serious psychiatric adverse experiences have been reported in patients treated with EFV, a component of Symfi Lo. In controlled trials of 1008 patients treated with regimens containing EFV for a mean of 2.1 years and 635 patients treated with control regimens for a mean of 1.5 years, the frequency (regardless of causality) of specific serious psychiatric events among patients who received EFV or control regimens, respectively, were severe depression (2.4%, 0.9%), suicidal ideation (0.7%, 0.3%), nonfatal suicide attempts (0.5%, 0), aggressive behavior (0.4%, 0.5%), paranoid reactions (0.4%, 0.3%), and manic reactions (0.2%, 0.3%). 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. Other factors associated with an increase in the occurrence of these psychiatric symptoms were history of injection drug use, psychiatric history, and receipt of psychiatric medication at study entry; similar associations were observed in both the EFV and control treatment groups. In a study using EFV 600 mg, onset of new serious psychiatric symptoms occurred throughout the study for both EFV-treated and control-treated patients. One percent of EFV-treated patients discontinued or interrupted treatment because of one or more of these selected psychiatric symptoms.

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%).

There have also been occasional postmarketing reports of death by suicide, delusions, psychosis-like behavior, although a causal relationship to the use of EFV cannot be determined from these reports [see Adverse Reactions (6.2)]. Postmarketing cases of catatonia have also been reported and may be associated with increased efavirenz exposure. Patients with serious psychiatric adverse experiences should seek immediate medical evaluation to assess the possibility that the symptoms may be related to the use of EFV, and if so, to determine whether the risks of continued therapy outweigh the benefits.

Nervous System Symptoms

Fifty-three percent (531/1008) of patients receiving EFV, a component of Symfi Lo, in controlled trials reported central nervous system symptoms (any grade, regardless of causality) compared to 25% (156/635) of patients receiving control regimens. These symptoms included, but were not limited to, dizziness (28.1% of the 1008 patients), insomnia (16.3%), impaired concentration (8.3%), somnolence (7.0%), abnormal dreams (6.2%), and hallucinations (1.2%). These symptoms were severe in 2.0% of patients and 2.1% of patients discontinued therapy as a result. These symptoms usually begin during the first or second day of therapy and generally resolve after the first 2 to 4 weeks of therapy. After 4 weeks of therapy, the prevalence of nervous system symptoms of at least moderate severity ranged from 5% to 9% in patients treated with regimens containing EFV and from 3% to 5% in patients treated with a control regimen. Inform patients that these common symptoms were likely to improve with continued therapy and were not predictive of subsequent onset of the less frequent psychiatric symptoms [see Warnings and Precautions (5.5)]. Dosing at bedtime may improve the tolerability of these nervous system symptoms [see Dosage and Administration (2.2)].

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

EFV, a component of Symfi Lo, may cause fetal harm when administered during the first trimester to a pregnant woman. Advise females of reproductive potential who are receiving EFV to avoid pregnancy [see Use in Specific Populations (8.1, 8.3)].

Skin and Systemic Hypersensitivity Reaction

In controlled clinical trials, 26% (266/1008) of patients treated with 600 mg EFV experienced new-onset skin rash compared with 17% (111/635) of patients treated in control groups. Rash associated with blistering, moist desquamation, or ulceration occurred in 0.9% (9/1008) of patients treated with EFV. The incidence of Grade 4 rash (e.g., erythema multiforme, Stevens-Johnson syndrome) in patients treated with EFV in all studies and expanded access was 0.1%. Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 2 weeks of initiating therapy with EFV (median time to onset of rash in adults was 11 days) and, in most patients continuing therapy with EFV, rash resolves within 1 month (median duration, 16 days). The discontinuation rate for rash in clinical trials was 1.7% (17/1008).

EFV can generally be reinitiated in patients interrupting therapy because of rash. EFV should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement, or fever. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash. For patients who have had a life-threatening cutaneous reaction (e.g., Stevens-Johnson syndrome), alternate therapy should be considered [see Contraindications (4)].

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

Postmarketing cases of hepatitis, including fulminant hepatitis progressing to liver failure requiring transplantation or resulting in death, have been reported in patients treated with EFV. Reports have included patients with underlying hepatic disease, including coinfection with hepatitis B or C, and patients without pre-existing hepatic disease or other identifiable risk factors.

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 [see Adverse Reactions (6.1) and Use in Specific Populations (8.7)].

Monitoring of liver enzymes before and during treatment is recommended for all patients [see Dosage and Administration (2.1)]. 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.

Risk of Hepatic Decompensation When Used with Interferon- and Ribavirin-Based Regimens

In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as 3TC, a component of Symfi Lo. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with 3TC in HIV-1/HCV co-infected patients [see Clinical Pharmacology (12.3)], hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and 3TC should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of 3TC should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh > 6). See the full prescribing information for interferon and ribavirin.

Pancreatitis

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 [see Adverse Reactions (6.1)].

Convulsions

Convulsions have been observed in patients receiving EFV, generally in the presence of known medical history of seizures [see Nonclinical Toxicology (13.2)]. 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 [see Drug Interactions (7.5)].

Lipid Elevations

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.

Bone Effects

Bone Mineral Density (BMD)

In clinical trials in HIV-1-infected adults, TDF was associated with slightly greater decreases in 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 [see Adverse Reactions (6.1)].

The effects of TDF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for adults who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained.

Mineralization Defects

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 [see Adverse Reactions (6.2)]. Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing TDF [see Warnings and Precautions (5.4)].

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including EFV, 3TC, and TDF. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

Fat Redistribution

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. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

QTc Prolongation

QTc prolongation has been observed with the use of EFV [see Drug Interactions (7.2, 7.5) and Clinical Pharmacology (12.2)]. Consider alternatives to products containing EFV when coadministered with a drug with a known risk of Torsade de Pointes or when administered to patients at higher risk of Torsade de Pointes.

The following adverse reactions are discussed in other sections of the labeling:

• Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.1)]. • Exacerbations of Hepatitis B [see Boxed Warning, Warnings and Precautions (5.2)]. • New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.4)]. • Psychiatric Symptoms [see Warnings and Precautions (5.5)]. • Nervous System Symptoms [see Warnings and Precautions (5.6)]. • Skin and Systemic Hypersensitivity Reaction [see Warnings and Precautions (5.8)]. • Hepatotoxicity [see Warnings and Precautions (5.9)]. • Hepatic Decompensation in Patients Co-infected with HIV-1 and Hepatitis C [see Warnings and Precautions (5.10)]. • Pancreatitis [see Warnings and Precautions (5.11)]. • Decreases in Bone Mineral Density [see Warnings and Precautions (5.14)]. • Immune Reconstitution Syndrome [see Warnings and Precautions (5.15)]. • Fat Redistribution [see Warnings and Precautions (5.16)].

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, the adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate

Treatment-Naïve Patients

Study 903 - Adverse Reactions: The most common adverse reactions seen in a double-blind comparative controlled study in which 600 treatment-naïve subjects received TDF (N = 299) or stavudine (d4T) (N = 301) in combination with 3TC and EFV for 144 weeks were mild to moderate gastrointestinal events and dizziness.

Mild adverse reactions (Grade 1) were common with a similar incidence in both arms, and included dizziness, diarrhea, and nausea. Selected moderate to severe adverse reactions are summarized in Table 1.

Table 1. Selected Adverse Reactions* (Grades 2-4) Reported in ≥ 5% in Any Treatment Group in Study 903 (0-144 Weeks)

* Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. † Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome. ‡ Peripheral neuropathy includes peripheral neuritis and neuropathy. § Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash.
	TDF + 3TC + EFV	d4T + 3TC + EFV
	N = 299	N = 301
Body as a Whole
Headache	14%	17%
Pain	13%	12%
Fever	8%	7%
Abdominal pain	7%	12%
Back pain	9%	8%
Asthenia	6%	7%
Digestive System
Diarrhea	11%	13%
Nausea	8%	9%
Dyspepsia	4%	5%
Vomiting	5%	9%
Metabolic Disorders
Lipodystrophy†	1%	8%
Musculoskeletal
Arthralgia	5%	7%
Myalgia	3%	5%
Nervous System
Depression	11%	10%
Insomnia	5%	8%
Dizziness	3%	6%
Peripheral neuropathy‡	1%	5%
Anxiety	6%	6%
Respiratory
Pneumonia	5%	5%
Skin and Appendages
Rash event§	18%	12%

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 Table 2.

Table 2. Selected Adverse Reactions*(Grades 2-4) Reported in ≥ 2% in Either Treatment Group in the ENCORE1 Study through Week 48

* Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. † 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.
	EFV 400 mg + FTC/TDF	EFV 600 mg + FTC/TDF
	N = 321	N = 309
Rash event†	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%

Laboratory Abnormalities

With the exception of fasting cholesterol and fasting triglyceride elevations that were more common in the stavudine group (40% and 9%) compared with TDF (19% and 1%) respectively, laboratory abnormalities observed in this study occurred with similar frequency in the tenofovir disoproxil fumarate and stavudine treatment arms. A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 3.

Table 3. Grade 3/4 Laboratory Abnormalities Reported in ≥ 1% of Patients Randomized to Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate in Study 903 (0-144 Weeks)

	TDF + 3TC + EFV	d4T + 3TC + EFV
	N = 299	N = 301
Any ≥ Grade 3 Laboratory Abnormality	36%	42%
Fasting Cholesterol (> 240 mg/dL)	19%	40%
Creatine Kinase (M: > 990 U/L; F: > 845 U/L)	12%	12%
Serum Amylase (> 175 U/L)	9%	8%
AST (M: > 180 U/L; F: > 170 U/L)	5%	7%
ALT (M: > 215 U/L; F: > 170 U/L)	4%	5%
Hematuria (> 100 RBC/HPF)	7%	7%
Neutrophils (< 750/mm3)	3%	1%
Fasting Triglycerides (> 750 mg/dL)	1%	9%

In ENCORE1 study, a summary of Grade 3 and 4 laboratory abnormalities is provided in Table 4.

Table 4. 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%

Pancreatitis

Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral nucleoside-experienced pediatric subjects receiving 3TC alone or in combination with other antiretroviral agents [see Warnings and Precautions (5.11)].

Changes in Bone Mineral Density

In HIV-1-infected adult subjects in Study 903, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving TDF + 3TC + EFV (-2.2% ± 3.9) compared with subjects receiving d4T + 3TC + EFV (-1.0% ± 4.6) through 144 weeks. Changes in BMD at the hip were similar between the two treatment groups (-2.8% ± 3.5 in the TDF group vs. -2.4% ± 4.5 in the d4T group). In both groups, the majority of the reduction in BMD occurred in the first 24-48 weeks of the trial and this reduction was sustained through Week 144. Twenty-eight percent of TDF-treated subjects vs. 21% of the d4T-treated subjects lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 subjects in the TDF group and 6 subjects in the d4T group. In addition, there were significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C telopeptide, and urinary N telopeptide) and higher serum parathyroid hormone levels and 1,25 Vitamin D levels in the TDF group relative to the d4T group; however, except for bone-specific alkaline phosphatase, these changes resulted in values that remained within the normal range [see Warnings and Precautions (5.14)].

Postmarketing Experience

The following adverse reactions have been identified during post-approval use for each of the individual components of Symfi Lo (EFV, 3TC, and TDF). Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to EFV, 3TC, and TDF.

Efavirenz

Body as a Whole: allergic reactions, asthenia, redistribution/accumulation of body fat [see Warnings and Precautions (5.16)].

Central and Peripheral Nervous System: abnormal coordination, ataxia, cerebellar coordination and balance disturbances, convulsions, hypoesthesia, paresthesia, neuropathy, tremor, vertigo.

Endocrine: gynecomastia.

Gastrointestinal: constipation, malabsorption.

Cardiovascular: flushing, palpitations.

Liver and Biliary System: hepatic enzyme increase, hepatic failure, hepatitis.

Metabolic and Nutritional: hypercholesterolemia, hypertriglyceridemia.

Musculoskeletal: arthralgia, myalgia, myopathy.

Psychiatric: aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide, catatonia.

Respiratory: dyspnea.

Skin and Appendages: erythema multiforme, photoallergic dermatitis, Stevens-Johnson syndrome.

Special Senses: abnormal vision, tinnitus.

Lamivudine

Body as a Whole: redistribution/accumulation of body fat [see Warnings and Precautions (5.16)].

Endocrine and Metabolic: hyperglycemia.

General: weakness.

Hemic and Lymphatic: anemia (including pure red cell aplasia and severe anemias progressing on therapy).

Hepatic and Pancreatic: lactic acidosis and hepatic steatosis, posttreatment exacerbation of hepatitis B [see Boxed Warning, Warnings and Precautions (5.1, 5.2)].

Hypersensitivity: anaphylaxis, urticaria.

Musculoskeletal: muscle weakness, CPK elevation, rhabdomyolysis.

Skin: Alopecia, pruritus.

Tenofovir Disoproxil Fumarate

Immune System Disorders: allergic reaction, including angioedema.

Metabolism and Nutrition Disorders: lactic acidosis, hypokalemia, hypophosphatemia.

Respiratory, Thoracic, and Mediastinal Disorders: dyspnea.

Gastrointestinal Disorders: pancreatitis, increased amylase, abdominal pain.

Renal and Urinary Disorders: renal insufficiency, acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria [see Warnings and Precautions (5.4)].

Hepatobiliary Disorders: hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT).

Skin and Subcutaneous Tissue Disorders: rash.

Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy.

General Disorders and Administration Site Conditions: asthenia.

The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.

If overdose occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.

Efavirenz: Some patients accidentally taking 600 mg twice daily have reported increased nervous system symptoms. One patient experienced involuntary muscle contractions.

Treatment of overdose with EFV should consist of general supportive measures, including monitoring of vital signs and observation of the patient’s clinical status. Administration of activated charcoal may be used to aid removal of unabsorbed drug. There is no specific antidote for overdose with efavirenz. Since efavirenz is highly protein bound, dialysis is unlikely to significantly remove the drug from blood.

Lamivudine: There is no known specific treatment for overdose with 3TC. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required because a negligible amount of 3TC was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a 3TC overdose event.

Tenofovir Disoproxil Fumarate: Limited clinical experience at doses higher than the therapeutic dose of TDF 300 mg is available.

Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of tenofovir disoproxil fumarate, a 4-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

Symfi Lo (efavirenz, lamivudine and tenofovir disoproxil fumarate) is a fixed-dose combination tablet for oral administration. Each tablet contains 400 mg of efavirenz, 300 mg of lamivudine and 300 mg of tenofovir disoproxil fumarate, which is equivalent to 245 mg of tenofovir disoproxil. Each tablet contains the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, sodium lauryl sulfate, talc, titanium dioxide and yellow iron oxide.

Efavirenz: Efavirenz is an HIV-1 specific, non-nucleoside, reverse transcriptase inhibitor (NNRTI). Efavirenz is chemically described as (S)-6-Chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one. Its molecular formula is C14H9ClF3NO2 and its structural formula is:

Efavirenz is a white to slightly pink crystalline powder with a molecular mass of 315.67. It is soluble in methanol and practically insoluble in water (< 10 microgram/mL).

Lamivudine: Lamivudine (also known as 3TC) is a synthetic nucleoside analogue with activity against HIV-1 and HBV. The chemical name of lamivudine is (-)-1-[(2R,5S)-2-(Hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2′,3′-dideoxy, 3′-thiacytidine. It has a molecular formula of C8H11N3O3S and a molecular weight of 229.26 g per mol. It has the following structural formula:

Lamivudine is a white to off-white solid with a solubility of approximately 70 mg per mL in water at 20°C.

Tenofovir Disoproxil Fumarate: Tenofovir disoproxil fumarate (a prodrug of tenofovir) is a fumaric acid salt of bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. In vivo tenofovir disoproxil fumarate is converted to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5’-monophosphate. Tenofovir exhibits activity against HIV-1 reverse transcriptase.

The chemical name of tenofovir disoproxil fumarate is 9-[(R)-2-[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C19H30N5O10P•C4H4O4 and a molecular weight of 635.51. It has the following structural formula:

Tenofovir disoproxil fumarate is a white to off-white powder that is freely soluble in dimethylformamide and soluble in methanol. It has an octanol/phosphate buffer (pH 6.5) partition coefficient (log p) of 1.25 at 25°C.

NDC 49502-425-93   Rx only

Symfi LoTM
(efavirenz, lamivudine,
and tenofovir disoproxil
fumarate) tablets
400 mg/300 mg/300 mg*

Note to pharmacist: Do not cover
ALERT box with pharmacy label.

ALERT: Find out about
medicines that should NOT
be taken with Symfi Lo™.

30 tablets

*Each film-coated tablet contains:
Efavirenz, USP    400 mg
Lamivudine, USP     300 mg
Tenofovir Disoproxil Fumarate     300 mg
(equivalent to 245 mg of tenofovir
disoproxil)

Usual Dosage: See accompanying
prescribing information.

Keep this and all medication
out of the reach of children.

Store below 30°C (86°F).

Dispense only in original container.

Keep container tightly closed.

Manufactured in India for:
Mylan Specialty L.P.
Morgantown, WV 26505 U.S.A.

Made in India

Code No.: MP/DRUGS/25/1/2014

MS:MXI:42593:1C:R1

Symfi Lo  efavirenz, lamivudine and tenofovir disoproxil fumarate tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:49502-425 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength EFAVIRENZ (EFAVIRENZ) EFAVIRENZ 400 mg LAMIVUDINE (LAMIVUDINE) LAMIVUDINE 300 mg TENOFOVIR DISOPROXIL FUMARATE (TENOFOVIR ANHYDROUS) TENOFOVIR DISOPROXIL FUMARATE 300 mg

Inactive Ingredients Ingredient Name Strength CROSCARMELLOSE SODIUM   HYDROXYPROPYL CELLULOSE, UNSPECIFIED   LACTOSE MONOHYDRATE   MAGNESIUM STEARATE   MICROCRYSTALLINE CELLULOSE   POLYETHYLENE GLYCOL, UNSPECIFIED   POLYVINYL ALCOHOL, UNSPECIFIED   SODIUM LAURYL SULFATE   TALC   TITANIUM DIOXIDE   FERRIC OXIDE YELLOW

Product Characteristics Color WHITE (white to off-white) Score no score Shape OVAL Size 21mm Flavor Imprint Code M;TLE Contains

Packaging # Item Code Package Description 1 NDC:49502-425-93 1 BOTTLE, PLASTIC in 1 CARTON 1 30 TABLET, FILM COATED in 1 BOTTLE, PLASTIC

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA208255 03/13/2018

Labeler - Mylan Specialty L.P. (194775557)

Revised: 02/2018   Mylan Specialty L.P.

The U.S. Food and Drug Administration (FDA) has approved Symfi Lo (efavirenz, lamivudine and tenofovir disoproxil fumarate), a three-drug combination of a non-nucleoside reverse transcriptase inhibitor (efavirenz), and two nucleo(t)side reverse transcriptase inhibitors (lamivudine and tenofovir disoproxil fumarate) indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection.

Symfi Lo is a prescription medicine that is used without other antiviral medicines to treat Human Immunodeficiency Virus-1 (HIV-1) in people weighing at least 35 kg.

HIV-1 is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).

Symfi Lo contains the prescription medicines efavirenz, lamivudine and tenofovir disoproxil fumarate.

Symfi Lo is not for use in children weighing less than 35 kg.

• Store the tablets below 86°F (30°C).
• Keep the tablets in the original container.

Keep all medicines out of the reach of children and pets.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use this medicine for a condition for which it was not prescribed. Do not give it to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information that is written for health professionals.

You should not use this medicine if:

• you also take elbasvir and grazoprevir (for hepatitis C); or

• you are allergic to antiviral medicines that contain efavirenz, lamivudine, or tenofovir (such as Atripla, Combivir, Epivir, Sustiva, Trizivir, or Triumeq).

Tell your doctor if you have ever had:

• liver disease (especially hepatitis B or C); or

• kidney disease (or if you are on dialysis);

• mental illness or psychosis;

• heart problems;

• long QT syndrome (in you or a family member);

• drug or alcohol addiction;

• a seizure; or

• fractures or other problems with your bones.

Use effective birth control to prevent pregnancy while you are using Symfi Lo and for at least 12 weeks after your last dose. Symfi Lo could harm an unborn baby or cause birth defects. You may need to have a negative pregnancy test before starting this treatment.

Use two forms of birth control to prevent pregnancy, including a barrier form such as a condom or a diaphragm with spermicide.

Women with HIV or AIDS should not breast feed a baby. Even if your baby is born without HIV, the virus may be passed to the baby in your breast milk.

Efavirenz, lamivudine, and tenofovir combination is used alone to treat human immunodeficiency virus (HIV) infection. HIV is the virus that causes acquired immune deficiency syndrome (AIDS).

This medicine does not cure or prevent HIV or AIDS. It helps keep HIV from reproducing and appears to slow down the destruction of the immune system. This may help delay the development of problems that usually result from AIDS or HIV disease. It will not keep you from spreading HIV to other people. People who receive this medicine may continue to have some of the problems usually related to AIDS or HIV disease.

This medicine is available only with your doctor's prescription.