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mechanism of action is Cytochrome P450 3A4 Inhibitors [MoA], Cytochrome P450 2C9 Inhibitors [MoA], Cytochrome P450 2B6 Inducers [MoA], Non-Nucleoside Reverse Transcriptase Inhibitors [MoA], Nucleoside Reverse Transcriptase Inhibitors [MoA], Cytochrome P450 2C19 Inhibitors [MoA] or Cytochrome P450 3A Inducers [MoA]

Efavirenz, Emtricitabine And Tenofovir Disoproxil Fumarate

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Efavirenz, Emtricitabine And Tenofovir Disoproxil Fumarate Prescribing Information

Severe acute exacerbations of hepatitis B virus (HBV) have been reported in patients who

are coinfected with HIV-1 and HBV and

have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF), which are components of Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet.

Closely monitor hepatic function with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet. If appropriate, initiation of anti-hepatitis B therapy may be warranted

[see Warnings and Precautions (

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

All patients should be tested for the presence of chronic HBV before or when initiating antiretroviral therapy

[see Dosage and Administration ]

. Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued FTC or TDF, two of the components of Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet. Patients who are coinfected with HIV-1 and HBV should be closely monitored, with both clinical and laboratory follow-up for at least several months after stopping treatment with Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet. If appropriate, initiation of anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

)]

Warnings and Precautions

Nervous System Symptoms (

5.6 Nervous System Symptoms

Fifty-three percent (531/1,008) of subjects receiving EFV in controlled trials reported central nervous system symptoms (any grade, regardless of causality) compared to 25% (156/635) of subjects receiving control regimens. These symptoms included dizziness (28.1% of the 1,008 subjects), insomnia (16.3%), impaired concentration (8.3%), somnolence (7.0%), abnormal dreams (6.2%), and hallucinations (1.2%). Other reported symptoms were euphoria, confusion, agitation, amnesia, stupor, abnormal thinking, and depersonalization. The majority of these symptoms were mild to moderate (50.7%); symptoms were severe in 2.0% of subjects. Overall, 2.1% of subjects discontinued therapy as a result. These symptoms usually begin during the first or second day of therapy and generally resolve after the first 2‑4 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 subjects treated with regimens containing EFV and from 3% to 5% in subjects treated with a control regimen. Patients should be informed 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 ]

. Dosing at bedtime may improve the tolerability of these nervous system symptoms

[see Dosage and Administration ]

Analysis of long-term data from Study 006 showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among EFV‑treated subjects were generally similar to those in the indinavir-containing control arm.

Late-onset neurotoxicity, including ataxia and encephalopathy (impaired consciousness, confusion, psychomotor slowing, psychosis, delirium), may occur months to years after beginning EFV therapy. Some events of late-onset neurotoxicity have occurred in patients with CYP2B6 genetic polymorphisms which are associated with increased EFV levels despite standard dosing of EFV. 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 EFV use, and whether discontinuation of Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet is warranted.

Patients receiving Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet should be alerted to the potential for additive central nervous system effects when Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet is used concomitantly with alcohol or psychoactive drugs.

Patients who experience central nervous system symptoms such as dizziness, impaired concentration, and/or drowsiness should avoid potentially hazardous tasks such as driving or operating machinery.

) 10/2019

Immune Reconstitution Syndrome (

5.12 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including the components of Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet. 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, Guillain-Barre syndrome, and autoimmune hepatitis) 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.

) 10/2019

Testing: Consult Full Prescribing Information for important testing recommendations prior to initiation and during treatment with Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet. (
2.1 Testing Prior to Initiation and During Treatment with Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet
Prior to or when initiating Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet, test patients for hepatitis B virus infection
[see Warnings and Precautions ].
Prior to initiation and during use of Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus
[see Warnings and Precautions ].
Monitor hepatic function prior to and during treatment with Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet
[see Warnings and Precautions ].
Perform pregnancy testing before initiation of Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet in adolescents and adults of childbearing potential
[see Warnings and Precautions , Use in Specific Populations ].
)
Recommended dosage in adults and pediatric patients weighing at least 40 kg: One tablet once daily taken orally on an empty stomach, preferably at bedtime. (
2.2 Recommended Dosage for Adults and Pediatric Patients Weighing at Least 40 kg
Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet is a three-drug fixed-dose combination product containing 600 mg of efavirenz (EFV), 200 mg of emtricitabine (FTC), and 300 mg of tenofovir disoproxil fumarate (TDF). The recommended dosage of Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet in adults and pediatric patients weighing at least 40 kg is one tablet once daily taken orally on an empty stomach. Dosing at bedtime may improve the tolerability of nervous system symptoms
[see Clinical Pharmacology ].
)
Renal impairment: Not recommended in patients with estimated creatinine clearance below 50 mL/min. (
2.3 Not Recommended in Patients with Moderate or Severe Renal Impairment
Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet is not recommended in patients with moderate or severe renal impairment (estimated creatinine clearance below 50 mL/min)
[see Warnings and Precautions , Use in Specific Populations ].
)
Hepatic impairment: Not recommended in patients with moderate to severe hepatic impairment. (
2.4 Not Recommended in Patients with Moderate to Severe Hepatic Impairment
Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet is not recommended in patients with moderate to severe hepatic impairment (Child-Pugh B or C)
[see Warnings and Precautions and Use in Specific Populations ].
)
Dosage adjustment with rifampin coadministration: An additional 200 mg/day of efavirenz is recommended for patients weighing 50 kg or more. (
2.5 Dosage Adjustment with Rifampin
If Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet is co-administered with rifampin in patients weighing 50 kg or more, take one tablet of Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet once daily followed by one additional 200 mg per day of efavirenz
[see Drug Interactions and Clinical Pharmacology ].
)

Pregnancy: Avoid pregnancy while receiving Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate and for 12 weeks after discontinuation. (
5.8 Embryo-Fetal Toxicity
Efavirenz may cause fetal harm when administered during the first trimester of pregnancy. Advise adults and adolescents of childbearing potential who are receiving Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet to avoid pregnancy while receiving Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet and for 12 weeks after discontinuation
[see Dosage and Administration , Use in Specific Populations ]
.
,
8.3 Females and Males of Reproductive Potential
Pregnancy Testing
Perform pregnancy testing in adults and adolescents of childbearing potential before initiation of Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet because of potential risk of neural tube defects
[see Use in Specific Populations ]
.
Contraception
Advise adults and adolescents of childbearing potential to use effective contraception during treatment with Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet and for 12 weeks after discontinuing Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet due to the long half-life of EFV, a component of Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet. Hormonal methods that contain progesterone may have decreased effectiveness Always use barrier contraception in combination with other methods of contraception
[see Drug Interactions
]
.
)
Lactation: Breastfeeding is not recommended. (
8.2 Lactation
Risk Summary
The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1.
Based on limited published data, EFV, FTC, and tenofovir have been shown to be present in human breast milk. It is not known if the components of Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet affect milk production or have effects on the breastfed child. Because of the potential for: (1) HIV transmission (in HIV-negative infants); (2) developing viral resistance (in HIV-positive infants); and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet .
)
Females and Males of Reproductive Potential: Pregnancy testing and contraception are recommended. (
8.3 Females and Males of Reproductive Potential
Pregnancy Testing
Perform pregnancy testing in adults and adolescents of childbearing potential before initiation of Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet because of potential risk of neural tube defects
[see Use in Specific Populations ]
.
Contraception
Advise adults and adolescents of childbearing potential to use effective contraception during treatment with Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet and for 12 weeks after discontinuing Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet due to the long half-life of EFV, a component of Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet. Hormonal methods that contain progesterone may have decreased effectiveness Always use barrier contraception in combination with other methods of contraception
[see Drug Interactions
]
.
)

Pediatrics: The incidence of rash was higher than in adults. (

5.2 Rash

In controlled clinical trials, 26% (266/1,008) of adult subjects treated with 600 mg EFV experienced new-onset skin rash compared with 17% (111/635) of those treated in control groups. Rash associated with blistering, moist desquamation, or ulceration occurred in 0.9% (9/1,008) of subjects treated with EFV. The incidence of Grade 4 rash (e.g., erythema multiforme, Stevens-Johnson syndrome) in adult subjects treated with EFV in all trials 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 subjects continuing therapy with EFV, rash resolves within 1 month (median duration, 16 days). The discontinuation rate for rash in adult clinical trials was 1.7% (17/1,008). Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet can be reinitiated in patients interrupting therapy because of rash. Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet 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), alternative therapy should be considered

[see Contraindications ]

Experience with EFV in subjects who discontinued other antiretroviral agents of the NNRTI class is limited. Nineteen subjects who discontinued nevirapine because of rash have been treated with EFV. Nine of these subjects developed mild-to-moderate rash while receiving therapy with EFV, and two of these subjects discontinued because of rash.

Rash was reported in 59 of 182 pediatric subjects (32%) treated with EFV

[see Adverse Reactions ]

. Two pediatric subjects experienced Grade 3 rash (confluent rash with fever, generalized rash), and four subjects had Grade 4 rash (erythema multiforme). The median time to onset of rash in pediatric subjects was 28 days (range 3-1,642 days). Prophylaxis with appropriate antihistamines before initiating therapy with Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet in pediatric patients should be considered.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the 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.

Clinical Trials in Adult Subjects

Study 934 was an open-label active-controlled trial in which 511 antiretroviral-naive subjects received either FTC + TDF administered in combination with EFV (N=257) or zidovudine (AZT)/lamivudine (3TC) administered in combination with EFV (N=254).

The most common adverse reactions (incidence greater than or equal to 10%, any severity) occurring in Study 934 include diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. Adverse reactions observed in Study 934 were generally consistent with those seen in previous trials of the individual components (Table 1).

Table 1: Selected Adverse Reactions^a(Grades 2-4) Reported in ≥5% in Either Treatment Group in Study 934 (0-144 Weeks)
	FTC+TDF+EFV^b	AZT/3TC+EFV
	N=257	N=254
Fatigue	9%	8%
Depression	9%	7%
Nausea	9%	7%
Diarrhea	9%	5%
Dizziness	8%	7%
Upper respiratory tract infections	8%	5%
Sinusitis	8%	4%
Rash Event^c	7%	9%
Headache	6%	5%
Insomnia	5%	7%
Anxiety	5%	4%
Nasopharyngitis	5%	3%
Vomiting	2%	5%
^a.Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. ^b.From Weeks 96 to 144 of the trial, subjects received FTC/TDF administered in combination with EFV in place of FTC+ TDF with EFV. ^c.Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculopapular, rash pruritic, and rash vesicular.

In Study 073, subjects with stable, virologic suppression on antiretroviral therapy and no history of virologic failure were randomized to receive Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet or to stay on their baseline regimen. The adverse reactions observed in Study 073 were generally consistent with those seen in Study 934 and those seen with the individual components of Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet when each was administered in combination with other antiretroviral agents.

Efavirenz, Emtricitabine, or TDF

In addition to the adverse reactions in Study 934 and Study 073, the following adverse reactions were observed in clinical trials of EFV, FTC, or TDF in combination with other antiretroviral agents.

Efavirenz:

The most significant adverse reactions observed in subjects treated with EFV were nervous system symptoms

[see Warnings and Precautions ]

, psychiatric symptoms

[see Warnings and Precautions ]

, and rash

[see Warnings and Precautions ]

Selected adverse reactions of moderate-to-severe intensity observed in greater than or equal to 2% of EFV-treated subjects in two controlled clinical trials included pain, impaired concentration, abnormal dreams, somnolence, anorexia, dyspepsia, abdominal pain, nervousness, and pruritus.

Pancreatitis has also been reported, although a causal relationship with EFV has not been established. Asymptomatic increases in serum amylase levels were observed in a significantly higher number of subjects treated with EFV 600 mg than in control subjects.

Skin discoloration has been reported with higher frequency among FTC-treated subjects; it was manifested by hyperpigmentation on the palms and/or soles and was generally mild and asymptomatic. The mechanism and clinical significance are unknown.

Clinical Trials in Pediatric Subjects

Efavirenz:

Assessment of adverse reactions is based on three pediatric clinical trials in 182 HIV-1 infected pediatric subjects who received EFV in combination with other antiretroviral agents for a median of 123 weeks. The type and frequency of adverse reactions in the three trials were generally similar to that of adult subjects with the exception of a higher incidence of rash, which was reported in 32% (59/182) of pediatric subjects compared to 26% of adults, and a higher frequency of Grade 3 or 4 rash reported in 3% (6/182) of pediatric subjects compared to 0.9% of adults

[see Warnings and Precautions ]

Emtricitabine:

In addition to the adverse reactions reported in adults, anemia and hyperpigmentation were observed in 7% and 32%, respectively, of pediatric subjects who received treatment with FTC in the larger of two open-label, uncontrolled pediatric trials (N=116).

Tenofovir DF:

In a pediatric clinical trial conducted in subjects 12 to less than 18 years of age, the adverse reactions observed in pediatric subjects who received treatment with TDF (N=81) were consistent with those observed in clinical trials of TDF in adults

[see Warnings and Precautions ]

Laboratory Abnormalities

Efavirenz, Emtricitabine and Tenofovir DF:

Laboratory abnormalities observed in Study 934 were generally consistent with those seen in previous trials (Table 2).

Table 2: Significant Laboratory Abnormalities Reported in ≥1% of Subjects in Either Treatment Group in Study 934 (0-144 Weeks)
^a.From Weeks 96 to 144 of the trial, subjects received FTC/TDF administered in combination with EFV in place of FTC + TDF with EFV.
	FTC + TDF + EFV^a	AZT/3TC + EFV
	N=257	N=254
Any ≥ Grade 3 Laboratory Abnormality	30%	26%
Fasting Cholesterol (>240 mg/dL)	22%	24%
Creatine Kinase (M: >990 U/L) (F: >845 U/L)	9%	7%
Serum Amylase (>175 U/L)	8%	4%
Alkaline Phosphatase (>550 U/L)	1%	0%
AST (M: >180 U/L) (F: >170 U/L)	3%	3%
ALT (M: >215 U/L) (F: >170 U/L)	2%	3%
Hemoglobin (<8.0 mg/dL)	0%	4%
Hyperglycemia (>250 mg/dL)	2%	1%
Hematuria (>75 RBC/HPF)	3%	2%
Glycosuria (≥3+)	<1%	1%
Neutrophils (<750/mm³)	3%	5%
Fasting Triglycerides (>750 mg/dL)	4%	2%

Laboratory abnormalities observed in Study 073 were generally consistent with those in Study 934.

Hepatic Events:

In Study 934, 19 subjects treated with EFV, FTC, and TDF and 20 subjects treated with EFV and fixed-dose zidovudine/lamivudine were hepatitis B surface antigen or hepatitis C antibody positive. Among these coinfected subjects, one subject (1/19) in the EFV, FTC, and TDF arm had elevations in transaminases to greater than five times ULN through 144 weeks. In the fixed-dose zidovudine/lamivudine arm, two subjects (2/20) had elevations in transaminases to greater than five times ULN through 144 weeks. No HBV and/or HCV coinfected subject discontinued from the trial due to hepatobiliary disorders

[see Warnings and Precautions ]

)

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Efavirenz, Emtricitabine And Tenofovir Disoproxil Fumarate

Efavirenz, Emtricitabine And Tenofovir Disoproxil Fumarate Prescribing Information

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