Drug Safety-related Labeling Changes (SrLC)

Get Email Alerts | Guide

ATRIPLA (NDA-021937)

(EFAVIRENZ; EMTRICITABINE; TENOFOVIR DISOPROXIL FUMARATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

Download Data

Expand all

10/29/2019 (SUPPL-44)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.12 Immune Reconstitution Syndrome

(additions underlined)

…

Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré  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.

5.6 Nervous System Symptoms

(additions underlined)

…

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 ATRIPLA is warranted.

…

6 Adverse Reactions

6.2 Postmarketing Experience

(addition underlined)

…

Nervous System Disorders

Abnormal coordination, ataxia, encephalopathy, cerebellar coordination and balance disturbances, convulsions, hypoesthesia, paresthesia, neuropathy, tremor

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(additions underlined)

…

 

Nervous System Symptoms

…

• Inform patients that there is a risk of developing late-onset neurotoxicity, including ataxia and encephalopathy, which may occur months to years after beginning therapy with EFV, a component of ATRIPLA.

 

…

PATIENT INFORMATION

(additions underlined)

…

Nervous system problems. Nervous system problems usually begin during the first or second day of treatment with ATRIPLA and usually go away after 2 to 4 weeks of treatment. Some symptoms may occur months to years after beginning ATRIPLA therapy. These symptoms may become more severe if you drink alcohol or take mood altering (street) drugs while taking ATRIPLA. Tell your healthcare provider right away if you develop nervous system problems during treatment with ATRIPLA. Symptoms of nervous system problems may include:

…

• slow thoughts and physical movement

…

• lack of coordination or difficulty with balance

If you have dizziness, trouble concentrating or sleepiness, do not drive a car, use machinery, or do anything that needs you to be alert .

07/25/2018 (SUPPL-43)

Approved Drug Label (PDF)

Boxed Warning

(Additions and/or revisions are underlined)

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 ATRIPLA. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

4 Contraindications

(Additions and/or revisions are underlined)

• ATRIPLA is contraindicated to be coadministered with voriconazole or elbasvir/grazoprevir.

5 Warnings and Precautions

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

(Additions and/or revisions are underlined)

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

5.11 Lactic Acidosis/Severe Hepatomegaly with Steatosis

(Additions and/or revisions are underlined)

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including TDF and FTC, components of ATRIPLA, alone or in combination with other antiretrovirals. Treatment with ATRIPLA 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).

5.2 Rash

(Additions and/or revisions are underlined)

…ATRIPLA can be reinitiated in patients interrupting therapy because of rash. ATRIPLA 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.

5.3 Hepatotoxicity

(Additions and/or revisions are underlined)

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, a component of ATRIPLA. 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.

ATRIPLA is not recommended for patients with moderate or severe hepatic impairment. Careful monitoring is recommended for patients with mild hepatic impairment receiving ATRIPLA.

Monitoring of liver enzymes before and during treatment is recommended for all patients. Consider discontinuing ATRIPLA in patients with persistent elevations of serum transaminases to greater than five times the upper limit  of the normal range. Discontinue ATRIPLA if elevation of serum transaminases is accompanied by clinical signs or symptoms of hepatitis or hepatic decompensation.

(Additions and/or revisions are underlined)

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, a component of ATRIPLA. 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.

ATRIPLA is not recommended for patients with moderate or severe hepatic impairment. Careful monitoring is recommended for patients with mild hepatic impairment receiving ATRIPLA.

Monitoring of liver enzymes before and during treatment is recommended for all patients. Consider discontinuing ATRIPLA in patients with persistent elevations of serum transaminases to greater than five times the upper limit of the normal range. Discontinue ATRIPLA if elevation of serum transaminases is accompanied by clinical signs or symptoms of hepatitis or hepatic decompensation.

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

(Additions and/or revisions are underlined)

The concomitant use of ATRIPLA and other drugs may result in potentially significant drug interactions, some of which may lead to:

• Loss of therapeutic effect of concomitant drug or ATRIPLA and possible development of resistance.

• Possible clinically significant adverse reaction from greater exposures of ATRIPLA or concomitant drug.

QTc prolongation has been observed with the use of EFV. Consider alternatives to ATRIPLA 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.

See Table 3 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during ATRIPLA therapy and review concomitant medications during ATRIPLA therapy.

5.5 Psychiatric Symptoms

(Additions and/or revisions are underlined)

Serious psychiatric adverse experiences have been reported in patients treated with EFV, a component of ATRIPLA. In controlled trials of 1,008 subjects treated with regimens containing EFV for a mean of 2.1 years and 635 subjects treated with control regimens for a mean of 1.5 years, the frequency (regardless of causality) of specific serious psychiatric events among subjects 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 Study AI266006 (006, NCT00002410), a Phase 3 randomized, open-label trial of EFV-containing regimens versus controls in 1,266 subjects (median follow-up 180 weeks, 102 weeks, and 76 weeks for subjects treated with EFV + zidovudine + lamivudine, EFV + indinavir, and indinavir + zidovudine + lamivudine, respectively), 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 trial entry; similar associations were observed in both the EFV and control treatment groups. In Study 006, onset of new serious psychiatric symptoms occurred throughout the trial for both EFV-treated and control-treated subjects. One percent of EFV-treated subjects discontinued or interrupted treatment because of one or more of these selected psychiatric symptoms. There have also been occasional postmarketing reports of death by suicide, delusions, and psychosis-like behavior, although a causal relationship to the use of EFV cannot be determined from these reports. Postmarketing cases of catatonia have also been reported and may be associated with increased EFV 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.

5.6 Nervous System Symptoms

(Additions and/or revisions are underlined)

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

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.

Patients receiving ATRIPLA should be alerted to the potential for additive central nervous system effects when ATRIPLA 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.

5.7 New Onset or Worsening Renal Impairment

(Additions and/or revisions are underlined)

Emtricitabine and tenofovir are principally eliminated by the kidney; however, EFV is not. 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, a component of ATRIPLA.

Prior to initiation and during use of ATRIPLA, 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. ATRIPLA is not recommended in patients with moderate or severe renal impairment (estimated creatinine clearance below 50 mL/min).

ATRIPLA should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs [NSAIDs]). 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 patients at risk of renal dysfunction.

Discontinue ATRIPLA in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

5.8 Embryo-Fetal Toxicity

(Additions and/or revisions are underlined)

Efavirenz may cause fetal harm when administered during the first trimester of pregnancy. Advise adults and adolescents of childbearing potential who are receiving ATRIPLA to avoid pregnancy while receiving ATRIPLA and for 12 weeks after discontinuation.

5.9 Bone Loss and Mineralization Defects

(Additions and/or revisions are underlined)

Bone Mineral Density

In clinical trials in HIV-1 infected adults, TDF (a component of ATRIPLA) 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…

6 Adverse Reactions

(Additions and/or revisions are underlined)

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

• Severe Acute Exacerbations of Hepatitis B, in Patients Coinfected with HIV-1 and HBV.

• Rash.

• Psychiatric Symptoms.

• Nervous System Symptoms.

• New Onset or Worsening Renal Impairment.

• Embryo-Fetal Toxicity.

• Bone Loss and Mineralization Defects.

• Lactic Acidosis/Severe Hepatomegaly with Steatosis.

• Immune Reconstitution Syndrome.

7 Drug Interactions

7.2 Drugs Affecting Renal Function

(Additions and/or revisions are underlined)

FTC and tenofovir are primarily eliminated by the kidneys. Coadministration of ATRIPLA with drugs that are eliminated by active tubular secretion may increase concentrations of FTC, tenofovir, and/or the coadministered drug. Some examples include, but are not limited to, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs. Drugs that decrease renal function may increase concentrations of FTC and/or tenofovir.

7.3 Established and Potentially Significant Interactions

(Extensive changes in Table 3; please refer to labeling)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Extensive Additions and/or revisions – please refer to labeling)

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

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 ATRIPLA 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 ATRIPLA.

8.3 Females and Males of Reproductive Potential

(Newly Added Subsection)

Pregnancy Testing

Perform pregnancy testing in adults and adolescents of childbearing potential before initiation of ATRIPLA because of potential risk of neural tube defects.

Contraception

Advise adults and adolescents of childbearing potential to use effective contraception during treatment with ATRIPLA and for 12 weeks after discontinuing ATRIPLA due to the long half-life of EFV, a component of ATRIPLA. Hormonal methods that contain progesterone may have decreased effectiveness Always use barrier contraception in combination with other methods of contraception.

8.4 Pediatric Use

(Additions and/or revisions are underlined)

The effectiveness and safety of ATRIPLA as a complete regimen for the treatment of HIV-1 infection was established in pediatric patients with body weight greater than or equal to 40 kg . Use of ATRIPLA in this age group is supported by adequate and well-controlled studies of ATRIPLA in adults with HIV-1 infection and data from pediatric studies of the individual components of ATRIPLA (EFV, FTC, and TDF).

ATRIPLA should only be administered to pediatric patients with a body weight greater than or equal to 40 kg. Because ATRIPLA is a fixed-dose combination tablet, the dose componentof ATRIPLA cannot be adjusted for patients of lower weight.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Extensive changes; please refer to labeling)

Patient Information ATRIPLA® (uh TRIP luh) (efavirenz, emtricitabine, and tenofovir disoproxil fumarate) tablets

(Extensive changes; please refer to labeling)

04/07/2017 (SUPPL-41)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.15 Fat Redistribution

(Additions and/or revisions are underlined)

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance," has been observed in patients receiving antiretroviral therapy, including efavirenz…

5.3 Lactic Acidosis/Severe Hepatomegaly with Steatosis

(Additions and/or revisions are underlined)

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir DF and emtricitabine, components of ATRIPLA, alone or in combination with other antiretrovirals.

5.4 Coadministration with Related Products

(Additions and/or revisions are underlined)

ATRIPLA is a fixed-dose combination of efavirenz, emtricitabine, and tenofovir DF. Do not coadminister ATRIPLA with other drugs containing emtricitabine, tenofovir DF, or tenofovir alafenamide, including COMPLERA, DESCOVY, EMTRIVA, GENVOYA, ODEFSEY, STRIBILD, TRUVADA, VEMLIDY, or VIREAD.

5.5 QTc Prolongation

(Additions and/or revisions are underlined)

QTc prolongation has been observed with the use of efavirenz. Consider alternatives to ATRIPLA 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.

5.6 Psychiatric Symptoms

(Additions and/or revisions are underlined)

…There have also been occasional postmarketing reports of death by suicide, delusions, psychosis-like behavior, and catatonia, although a causal relationship to the use of efavirenz cannot be determined from these reports…

6 Adverse Reactions

(Additions and/or revisions are underlined)

Efavirenz, Emtricitabine and Tenofovir DF: The following adverse reactions are discussed in other sections of the labeling:

• QTc Prolongation
• Fat Redistribution

6.3 Postmarketing Experience

(Additions and/or revisions are underlined)

Psychiatric Disorders

Aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide, catatonia

7 Drug Interactions

7.1 Efavirenz

(Additions and/or revisions are underlined)

There is limited information available on the potential for a pharmacodynamic interaction between efavirenz and drugs that prolong the QTc interval. QTc prolongation has been observed with the use of efavirenz . Consider alternatives to ATRIPLA when coadministered with a drug with a known risk of Torsade de Pointes.

7.3 Efavirenz, Emtricitabine and Tenofovir DF

Table 3 Established and Other Potentially Significant (superscript a) Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction

(Table has been revised; please refer to label)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Advise patients that:

• ATRIPLA should not be coadministered with COMPLERA, DESCOVY, EMTRIVA, GENVOYA, ODEFSEY, STRIBILD, TRUVADA, VEMLIDY, or VIREAD; or drugs containing lamivudine, including Combivir, Epivir, Epivir-HBV, Epzicom, or Trizivir. SUSTIVA should not be coadministered with ATRIPLA unless needed for dose adjustment.

Bone Effects of Tenofovir DF

…Advise patients that bone mineral density monitoring may be performed in patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss.

Psychiatric Symptoms

Inform patients that serious psychiatric symptoms including severe depression, suicide attempts, aggressive behavior, delusions, paranoia, psychosis-like symptoms, and catatonia have been reported in patients receiving efavirenz.

Patient Information

(Additions and/or revisions are underlined)

MEDICINES YOU SHOULD NOT TAKE WITH ATRIPLA

ATRIPLA also should not be used with Combivir (lamivudine/zidovudine), COMPLERA®, DESCOVY, EMTRIVA, Epivir, Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), GENVOYA, ODEFSEY, STRIBILD®, Trizivir (abacavir sulfate/lamivudine/zidovudine), TRUVADA, VEMLIDY, or VIREAD.

 

It is also important to tell your healthcare provider if you are taking any of the following:

• Fortovase, Invirase (saquinavir), Biaxin (clarithromycin), Noxafil (posaconazole), Sporanox (itraconazole), Victrelis (boceprevir), Olysio (simeprevir), or EPCLUSA (sofosbuvir/velpatasvir); these medicines may need to be replaced with another medicine when taken with ATRIPLA.
• Reyataz (atazanavir sulfate), Prezista (darunavir) with Norvir (ritonavir), Kaletra (lopinavir/ritonavir), EPCLUSA (sofosbuvir/velpatasvir) or HARVONI (ledipasvir/sofosbuvir); these medicines may increase the amount of tenofovir DF (a component of ATRIPLA) in your blood, which could result in more side effects. EPCLUSA and Reyataz are not recommended with ATRIPLA…

 

What are the possible side effects of ATRIPLA?

ATRIPLA may cause the following serious side effects:

• Too much lactic acid in your blood (lactic acidosis). Too much lactic acid is a serious but rare medical emergency that can lead to death. Tell your healthcare provider right away if you get these symptoms: weakness or being more tired than usual, unusual muscle pain, being short of breath or fast breathing, stomach pain with nausea and vomiting, cold or blue hands and feet, feel dizzy or lightheaded, or a fast or abnormal heartbeat.
• Severe liver problems. In rare cases, severe liver problems can happen that can lead to death. Tell your healthcare provider right away if you get these symptoms: skin or the white part of your eyes turns yellow, dark “tea-colored” urine, light-colored stools, loss of appetite for several days or longer, nausea, or stomach-area pain.

02/11/2016 (SUPPL-39)

Approved Drug Label (PDF)

7 Drug Interactions

NS5A inhibitor/NS5B polymerase inhibitor: ledipasvir/sofosbuvir

Patients receiving ATRIPLA and HARVONI (ledipasvir/sofosbuvir) concomitantly should be monitored for adverse reactions associated with tenofovir