7 This section describes clinically relevant drug interactions with ATRIPLA.
Drug interaction studies are described elsewhere in the labeling [ see Clinical Pharmacology (12.3) ].
Efavirenz: Coadministration of efavirenz can alter the concentrations of other drugs and other drugs may alter the concentrations of efavirenz.
The potential for drug-drug interactions must be considered before and during therapy.
( 4.2 , 7.1 , 12.3 ) Didanosine: Tenofovir disoproxil fumarate increases didanosine concentrations.
Use with caution and monitor for evidence of didanosine toxicity (e.g., pancreatitis, neuropathy) when coadministered.
Consider dose reductions or discontinuations of didanosine if warranted.
( 7.2 ) Atazanavir: Coadministration of ATRIPLA and atazanavir or atazanavir/ritonavir is not recommended.
( 7.3 ) Lopinavir/ritonavir: Coadministration increases tenofovir concentrations.
Monitor for evidence of tenofovir toxicity.
( 7.3 ) 7.1 Efavirenz Efavirenz has been shown in vivo to induce CYP3A.
Other compounds that are substrates of CYP3A may have decreased plasma concentrations when coadministered with efavirenz.
In vitro studies have demonstrated that efavirenz inhibits CYP2C9, 2C19, and 3A4 isozymes in the range of observed efavirenz plasma concentrations.
Coadministration of efavirenz with drugs primarily metabolized by these isozymes may result in altered plasma concentrations of the coadministered drug.
Therefore, appropriate dose adjustments may be necessary for these drugs.
Drugs that induce CYP3A activity (e.g., phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations.
7.2 Emtricitabine and Tenofovir Disoproxil Fumarate Since emtricitabine and tenofovir are primarily eliminated by the kidneys, coadministration of ATRIPLA with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of emtricitabine, tenofovir, and/or other renally eliminated drugs.
Some examples include, but are not limited to, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, and valganciclovir.
Coadministration of tenofovir DF and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions.
Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions [for didanosine dosing adjustment recommendations, see Table 4 ].
Suppression of CD4 + cell counts has been observed in patients receiving tenofovir DF with didanosine 400 mg daily.
Lopinavir/ritonavir has been shown to increase tenofovir concentrations.
The mechanism of this interaction is unknown.
Patients receiving lopinavir/ritonavir with ATRIPLA should be monitored for tenofovir-associated adverse reactions.
ATRIPLA should be discontinued in patients who develop tenofovir-associated adverse reactions [ See Table 4 ].
Coadministration of atazanavir with ATRIPLA is not recommended since coadministration of atazanavir with either efavirenz or tenofovir DF has been shown to decrease plasma concentrations of atazanavir.
Also, atazanavir has been shown to increase tenofovir concentrations.
There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA [ See Table 4 ].
7.3 Efavirenz, Emtricitabine and Tenofovir Disoproxil Fumarate Other important drug interaction information for ATRIPLA is summarized in Table 1 and Table 4.
The drug interactions described are based on studies conducted with efavirenz, emtricitabine or tenofovir DF as individual agents or are potential drug interactions; no drug interaction studies have been conducted using ATRIPLA [for pharmacokinetics data see Clinical Pharmacology (12.3) , Tables 5–9].
The tables include potentially significant interactions, but are not all inclusive.
Table 4 Established and Other Potentially Significant This table is not all inclusive.
Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction Concomitant Drug Class: Drug Name Effect Clinical Comment Antiretroviral agents Protease inhibitor: atazanavir ↓atazanavir concentration ↑ tenofovir concentration Coadministration of atazanavir with ATRIPLA is not recommended.
Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir.
The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known.
Also, atazanavir has been shown to increase tenofovir concentrations.
There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA.
Protease inhibitor: fosamprenavir calcium ↓ amprenavir concentration Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established.
Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily.
No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor: indinavir ↓ indinavir concentration The optimal dose of indinavir, when given in combination with efavirenz, is not known.
Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.
Protease inhibitor: lopinavir/ritonavir ↓ lopinavir concentration ↑ tenofovir concentration A dose increase of lopinavir/ritonavir to 600/150 mg (3 tablets) twice daily may be considered when used in combination with efavirenz in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence).
Patients should be monitored for tenofovir-associated adverse reactions.
ATRIPLA should be discontinued in patients who develop tenofovir-associated adverse reactions .
Protease inhibitor: ritonavir ↑ ritonavir concentration ↑ efavirenz concentration When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes).
Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir.
Protease inhibitor: saquinavir ↓ saquinavir concentration Should not be used as sole protease inhibitor in combination with ATRIPLA.
NRTI: didanosine ↑ didanosine concentration Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy.
In adults weighing >60 kg, the didanosine dose should be reduced to 250 mg if coadministered with ATRIPLA .
Data are not available to recommend a dose adjustment of didanosine for patients weighing <60 kg.
Coadministration of ATRIPLA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions.
For additional information, please consult the Videx / Videx EC (didanosine) prescribing information.
Other agents Anticoagulant: warfarin ↑ or ↓ warfarin concentration Plasma concentrations and effects potentially increased or decreased by efavirenz.
Anticonvulsants: carbamazepine ↓ carbamazepine concentration ↓ efavirenz concentration There are insufficient data to make a dose recommendation for ATRIPLA.
Alternative anticonvulsant treatment should be used.
phenytoin phenobarbital ↓ anticonvulsant concentration ↓ efavirenz concentration Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressant: sertraline ↓ sertraline concentration Increases in sertraline dose should be guided by clinical response.
Antifungals: itraconazole ↓ itraconazole concentration ↓ hydroxy-itraconazole concentration Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
ketoconazole ↓ ketoconazole concentration Drug interaction studies with ATRIPLA and ketoconazole have not been conducted.
Efavirenz has the potential to decrease plasma concentrations of ketoconazole.
Anti-infective: clarithromycin ↓ clarithromycin concentration ↑ 14-OH metabolite concentration Clinical significance unknown.
In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin.
No dose adjustment of ATRIPLA is recommended when given with clarithromycin.
Alternatives to clarithromycin, such as azithromycin, should be considered.
Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA.
Antimycobacterial: rifabutin ↓ rifabutin concentration Increase daily dose of rifabutin by 50%.
Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
Antimycobacterial: rifampin ↓ efavirenz concentration Clinical significance of reduced efavirenz concentration is unknown.
Dosing recommendations for concomitant use of ATRIPLA and rifampin have not been established.
Calcium channel blockers: diltiazem ↓ diltiazem concentration ↓ desacetyl diltiazem concentration ↓ N-monodes-methyl diltiazem concentration Diltiazem dose adjustments should be guided by clinical response (refer to the prescribing information for diltiazem).
No dose adjustment of ATRIPLA is necessary when administered with diltiazem.
Others (e.g., felodipine, nicardipine, nifedipine, verapamil) ↓ calcium channel blocker No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A.
The potential exists for reduction in plasma concentrations of the calcium channel blocker.
Dose adjustments should be guided by clinical response (refer to the prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors: atorvastatin pravastatin simvastatin ↓ atorvastatin concentration ↓ pravastatin concentration ↓ simvastatin concentration Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz.
Consult the prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives: Oral: Ethinyl estradiol/Norgestimate ↓ active metabolites of norgestimate A reliable method of barrier contraception must be used in addition to hormonal contraceptives.
Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased.
No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
Implant: Etonogestrel ↓ etonogestrel A reliable method of barrier contraception must be used in addition to hormonal contraceptives.
The interaction between etonogestrel and efavirenz has not been studied.
Decreased exposure of etonogestrel may be expected.
There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A ↓ immuno-suppressant Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz.
These immunosuppressants are not anticipated to affect exposure of efavirenz.
Dose adjustments of the immunosuppressant may be required.
Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA.
Narcotic analgesic: methadone ↓ methadone concentration Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal.
Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms.
Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.
7.4 Efavirenz Assay Interference Cannabinoid Test Interaction: Efavirenz does not bind to cannabinoid receptors.
False-positive urine cannabinoid test results have been observed in non-HIV-infected volunteers receiving efavirenz when the Microgenics Cedia DAU Multi-Level THC assay was used for screening.
Negative results were obtained when more specific confirmatory testing was performed with gas chromatography/mass spectrometry.
For more information, please consult the SUSTIVA prescribing information.
10 If overdose occurs, the patient should be monitored for evidence of toxicity, including monitoring of vital signs and observation of the patient’s clinical status; standard supportive treatment should then be applied as necessary.
Administration of activated charcoal may be used to aid removal of unabsorbed efavirenz.
Hemodialysis can remove both emtricitabine and tenofovir DF (refer to detailed information below), but is unlikely to significantly remove efavirenz from the blood.
Efavirenz: Some patients accidentally taking 600 mg twice daily have reported increased nervous system symptoms.
One patient experienced involuntary muscle contractions.
Emtricitabine: Limited clinical experience is available at doses higher than the therapeutic dose of emtricitabine.
In one clinical pharmacology study single doses of emtricitabine 1200 mg were administered to 11 subjects.
No severe adverse reactions were reported.
Hemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min).
It is not known whether emtricitabine can be removed by peritoneal dialysis.
Tenofovir Disoproxil Fumarate: Limited clinical experience at doses higher than the therapeutic dose of tenofovir DF 300 mg is available.
In one study, 600 mg tenofovir DF was administered to 8 subjects orally for 28 days, and no severe adverse reactions were reported.
The effects of higher doses are not known.
Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%.
Following a single 300 mg dose of tenofovir DF, a 4-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.
11 ATRIPLA is a fixed-dose combination tablet containing efavirenz, emtricitabine, and tenofovir disoproxil fumarate (tenofovir DF).
SUSTIVA is the brand name for efavirenz, a non-nucleoside reverse transcriptase inhibitor.
EMTRIVA is the brand name for emtricitabine, a synthetic nucleoside analog of cytidine.
VIREAD is the brand name for tenofovir DF, which is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate.
VIREAD and EMTRIVA are the components of TRUVADA.
ATRIPLA tablets are for oral administration.
Each tablet contains 600 mg of efavirenz, 200 mg of emtricitabine, and 300 mg of tenofovir DF (which is equivalent to 245 mg of tenofovir disoproxil) as active ingredients.
The tablets include the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate.
The tablets are film-coated with a coating material containing black iron oxide, polyethylene glycol, polyvinyl alcohol, red iron oxide, talc, and titanium dioxide.
Efavirenz: Efavirenz is chemically described as ( S )-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2 H -3,1-benzoxazin-2-one.
Its molecular formula is C 14 H 9 ClF 3 NO 2 and its structural formula is: Efavirenz is a white to slightly pink crystalline powder with a molecular mass of 315.68.
It is practically insoluble in water (<10 µg/mL).
Emtricitabine: The chemical name of emtricitabine is 5-fluoro-1-(2 R ,5 S )-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine.
Emtricitabine is the (-) enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5-position.
It has a molecular formula of C 8 H 10 FN 3 O 3 S and a molecular weight of 247.24.
It has the following structural formula: Emtricitabine is a white to off-white crystalline powder with a solubility of approximately 112 mg/mL in water at 25 o C.
Tenofovir Disoproxil Fumarate: Tenofovir DF is a fumaric acid salt of the bis -isopropoxycarbonyloxymethyl ester derivative of tenofovir.
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 C 19 H 30 N 5 O 10 P • C 4 H 4 O 4 and a molecular weight of 635.52.
It has the following structural formula: Tenofovir DF is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in water at 25 °C.
Chemical Structure Chemical Structure Chemical Structure
14 Clinical Study 934 supports the use of ATRIPLA tablets in antiretroviral treatment-naïve HIV-1 infected patients.
Additional data in support of the use of ATRIPLA in treatment- naive patients can be found in the prescribing information for VIREAD.
Clinical Study 073 provides clinical experience in subjects with stable, virologic suppression and no history of virologic failure who switched from their current regimen to ATRIPLA.
In antiretroviral treatment-experienced patients, the use of ATRIPLA tablets may be considered for patients with HIV-1 strains that are expected to be susceptible to the components of ATRIPLA as assessed by treatment history or by genotypic or phenotypic testing [See Clinical Pharmacology (12.4) ].
Study 934: Data through 144 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter study comparing emtricitabine + tenofovir DF administered in combination with efavirenz versus zidovudine/lamivudine fixed-dose combination administered in combination with efavirenz in 511 antiretroviral-naive subjects.
From weeks 96 to 144 of the study, subjects received emtricitabine/tenofovir DF fixed-dose combination with efavirenz in place of emtricitabine + tenofovir DF with efavirenz.
Subjects had a mean age of 38 years (range 18–80), 86% were male, 59% were Caucasian and 23% were Black.
The mean baseline CD4 + cell count was 245 cells/mm 3 (range 2–1191) and median baseline plasma HIV-1 RNA was 5.01 log 10 copies/mL (range 3.56–6.54).
Subjects were stratified by baseline CD4 + cell count (< or ≥ 200 cells/mm 3 ) and 41% had CD4 + cell counts <200 cells/mm 3 .
Fifty-one percent (51%) of subjects had baseline viral loads >100,000 copies/mL.
Treatment outcomes through 48 and 144 weeks for those subjects who did not have efavirenz resistance at baseline (n=487) are presented in Table 10.
Table 10 Outcomes of Randomized Treatment at Weeks 48 and 144 (Study 934) Outcomes At Week 48 At Week 144 FTC + TDF +EFV (N=244) AZT/3TC +EFV (N=243) FTC + TDF +EFV (N=227) Subjects who were responders at Week 48 or Week 96 (HIV-1 RNA <400 copies/mL) but did not consent to continue study after Week 48 or Week 96 were excluded from analysis.
AZT/3TC +EFV (N=229) Responder Subjects achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Weeks 48 and 144.
84% 73% 71% 58% Virologic failure Includes confirmed viral rebound and failure to achieve confirmed HIV-1 RNA <400 copies/mL through Weeks 48 and 144.
2% 4% 3% 6% Rebound 1% 3% 2% 5% Never suppressed 0% 0% 0% 0% Change in antiretroviral regimen 1% 1% 1% 1% Death <1% 1% 1% 1% Discontinued due to adverse event 4% 9% 5% 12% Discontinued for other reasons Includes lost to follow-up, patient withdrawal, noncompliance, protocol violation and other reasons.
10% 14% 20% 22% Through Week 48, 84% and 73% of subjects in the emtricitabine + tenofovir DF group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <400 copies/mL (71% and 58% through Week 144).
The difference in the proportion of subjects who achieved and maintained HIV-1 RNA <400 copies/mL through 48 weeks largely results from the higher number of discontinuations due to adverse events and other reasons in the zidovudine/lamivudine group in this open-label study.
In addition, 80% and 70% of subjects in the emtricitabine + tenofovir DF group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <50 copies/mL through Week 48 (64% and 56% through Week 144).
The mean increase from baseline in CD4 + cell count was 190 cells/mm 3 in the emtricitabine + tenofovir DF group and 158 cells/mm 3 in the zidovudine/lamivudine group at Week 48 (312 and 271 cells/mm 3 at Week 144).
Through 48 weeks, 7 subjects in the emtricitabine + tenofovir DF group and 5 subjects in the zidovudine/lamivudine group experienced a new CDC Class C event (10 and 6 subjects through 144 weeks).
Study 073: Study 073 was a 48-week open-label, randomized clinical trial in subjects with stable, virologic suppression on combination antiretroviral therapy consisting of at least two nucleoside reverse transcriptase inhibitors (NRTIs) administered in combination with a protease inhibitor (with or without ritonavir) or a non-nucleoside reverse transcriptase inhibitor (NNRTI).
To be enrolled, subjects were to have HIV-1 RNA <200 copies/mL for at least 12 weeks on their current regimen prior to study entry with no known HIV-1 substitutions conferring resistance to the components of ATRIPLA and no history of virologic failure.
The study compared the efficacy of switching to ATRIPLA or staying on the baseline antiretroviral regimen (SBR).
Subjects were randomized in a 2:1 ratio to switch to ATRIPLA (N=203) or stay on SBR (N=97).
Subjects had a mean age of 43 years (range 22 to 73 years), 88% were male, 68% were white, 29% were black or African-American, and 3% were of other races.
At baseline, median CD4 + cell count was 516 cells/mm 3 and 96% had HIV-1 RNA <50 copies/mL.
The median time since onset of antiretroviral therapy was 3 years and 88% of subjects were receiving their first antiretroviral regimen at study enrollment.
At Week 48, 89% and 87% of subjects who switched to ATRIPLA maintained HIV RNA <200 copies/mL and <50 copies/mL, respectively, compared to 88% and 85% who remained on SBR; this difference was not statistically significant.
No changes in CD4+ cell counts from baseline to Week 48 were observed in either treatment arm.
16 /STORAGE AND HANDLING ATRIPLA tablets are pink, capsule-shaped, film-coated, debossed with “123” on one side and plain-faced on the other side.
They are supplied by State of Florida DOH Central Pharmacy as follows: NDC Strength Quantity/Form Color Source NDC 53808-0208-1 600 mg / 200 mg / 300 mg 30 TABLET PINK 15584-0101-1 Store at 25 °C (77 °F); excursions permitted to 15–30 °C (59–86 °F) [see USP Controlled Room Temperature].
Keep container tightly closed.
Dispense only in original container.
Do not use if seal over bottle opening is broken or missing.
RECENT MAJOR CHANGES
Boxed Warning 1/2010 Warnings and Precautions Patients Coinfected with HIV-1 and HBV ( 5.2 ) 1/2010 New Onset or Worsening Renal Impairment ( 5.7 ) 1/2010 Reproductive Risk Potential ( 5.8 ) 1/2010 Decrease in Bone Mineral Density ( 5.11 ) 1/2010
8.5 Geriatric Use Clinical studies of efavirenz, emtricitabine, or tenofovir DF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
In general, dose selection for the elderly patients should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
DOSAGE FORMS AND STRENGTHS
3 ATRIPLA is available as tablets.
Each tablet contains 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate (tenofovir DF, which is equivalent to 245 mg of tenofovir disoproxil).
The tablets are pink, capsule-shaped, film-coated, debossed with “123” on one side and plain-faced on the other side.
Tablet containing 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate.
( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action ATRIPLA is a fixed-dose combination of antiviral drugs efavirenz, emtricitabine and tenofovir disoproxil fumarate.
[See Clinical Pharmacology (12.4) ].
INDICATIONS AND USAGE
1 ATRIPLA ® is indicated for use alone as a complete regimen or in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults.
ATRIPLA, a combination of 2 nucleoside analog HIV-1 reverse transcriptase inhibitors and 1 non-nucleoside HIV-1 reverse transcriptase inhibitor, is indicated for use alone as a complete regimen or in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults.
( 1 )
8.4 Pediatric Use ATRIPLA is not recommended for patients less than 18 years of age because it is a fixed-dose combination tablet containing a component, tenofovir DF, for which safety and efficacy have not been established in this age group.
8.1 Pregnancy Pregnancy Category D [See Warnings and Precautions (5.8) ]
8.3 Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV-1.
Studies in rats have demonstrated that both efavirenz and tenofovir are secreted in milk.
It is not known whether efavirenz, emtricitabine, or tenofovir is excreted in human milk.
Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving ATRIPLA.
WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS B Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate, a component of ATRIPLA, in combination with other antiretrovirals [See Warnings and Precautions (5.1) ].
ATRIPLA is not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of ATRIPLA have not been established in patients coinfected with HBV and HIV-1.
Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued EMTRIVA or VIREAD, which are components of ATRIPLA.
Hepatic function should be monitored closely 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 [See Warnings and Precautions (5.2) ] .
WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS B See full prescribing information for complete boxed warning.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate, a component of ATRIPLA.
( 5.1 ) ATRIPLA is not approved for the treatment of chronic hepatitis B virus (HBV) infection.
Severe acute exacerbations of hepatitis B have been reported in patients coinfected with HBV and HIV-1 who have discontinued EMTRIVA or VIREAD, two of the components of ATRIPLA.
Hepatic function should be monitored closely in these patients.
If appropriate, initiation of anti-hepatitis B therapy may be warranted.
( 5.2 )
WARNING AND CAUTIONS
Serious psychiatric symptoms: Immediate medical evaluation is recommended.
( 5.5 , 6.1 ) Nervous system symptoms (NSS): NSS are frequent, usually begin 1–2 days after initiating therapy and resolve in 2–4 weeks.
Dosing at bedtime may improve tolerability.
NSS are not predictive of onset of psychiatric symptoms.
( 2 , 5.6 ) New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome.
Assess creatinine clearance (CrCl) before initiating treatment with ATRIPLA.
Monitor CrCl and serum phosphorus in patients at risk.
Avoid administering ATRIPLA with concurrent or recent use of nephrotoxic drugs.
( 5.7 ) Pregnancy: Fetal harm can occur when administered to a pregnant woman during the first trimester.
Women should be apprised of the potential harm to the fetus.
( 5.8 ) Rash: Discontinue if severe rash develops.
( 5.9 , 6.1 ) Hepatotoxicity: Monitor liver function tests before and during treatment in patients with underlying hepatic disease, including hepatitis B and C, or marked transaminase elevations.
( 5.10 , 8.6 ) Decreases in bone mineral density (BMD): Consider monitoring BMD in patients with a history of pathological fracture or who are at risk for osteopenia.
( 5.11 ) Convulsions: Use caution in patients with a history of seizures.
( 5.12 ) Immune reconstitution syndrome: May necessitate further evaluation and treatment.
( 5.13 ) Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy.
( 5.14 ) Coadministration with other products: Do not use with drugs containing efavirenz, emtricitabine or tenofovir disoproxil fumarate including SUSTIVA, TRUVADA, EMTRIVA, VIREAD; or with drugs containing lamivudine.
Do not administer in combination with HEPSERA.
( 5.4 ) 5.1 Lactic Acidosis/Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs including tenofovir DF, a component of ATRIPLA, in combination with other antiretrovirals.
A majority of these cases have been in women.
Obesity and prolonged nucleoside exposure may be risk factors.
Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors.
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 Patients Coinfected with HIV-1 and HBV It is recommended that all patients with HIV-1 be tested for the presence of chronic HBV before initiating antiretroviral therapy.
ATRIPLA is not approved for the treatment of chronic HBV infection, and the safety and efficacy of ATRIPLA have not been established in patients coinfected with HBV and HIV-1.
Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued emtricitabine or tenofovir DF, two of the components of ATRIPLA.
In some patients infected with HBV and treated with emtricitabine, the exacerbations of hepatitis B were associated with liver decompensation and liver failure.
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.
ATRIPLA should not be administered with HEPSERA ® (adefovir dipivoxil) [See Drug Interactions (7.2) ] .
5.3 Drug Interactions Efavirenz plasma concentrations may be altered by substrates, inhibitors, or inducers of CYP3A.
Likewise, efavirenz may alter plasma concentrations of drugs metabolized by CYP3A [See Contraindications (4.2) , Drug Interactions (7.1) ] .
5.4 Coadministration with Related Products Related drugs not for coadministration with ATRIPLA include EMTRIVA (emtricitabine), VIREAD (tenofovir DF), TRUVADA (emtricitabine/tenofovir DF), and SUSTIVA (efavirenz), which contain the same active components as ATRIPLA.
Due to similarities between emtricitabine and lamivudine, ATRIPLA should not be coadministered with drugs containing lamivudine, including Combivir (lamivudine/zidovudine), Epivir, or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), or Trizivir (abacavir sulfate/lamivudine/zidovudine).
5.5 Psychiatric Symptoms Serious psychiatric adverse experiences have been reported in patients treated with efavirenz.
In controlled trials of 1008 subjects treated with regimens containing efavirenz 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 efavirenz 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), treatment with efavirenz 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 efavirenz and control treatment groups.
In Study 006, onset of new serious psychiatric symptoms occurred throughout the study for both efavirenz-treated and control-treated subjects.
One percent of efavirenz-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 efavirenz cannot be determined from these reports.
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 efavirenz, and if so, to determine whether the risks of continued therapy outweigh the benefits [See Adverse Reactions (6) ].
5.6 Nervous System Symptoms Fifty-three percent (531/1008) of subjects receiving efavirenz 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 1008 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-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 efavirenz 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 (5.5) ] .
Dosing at bedtime may improve the tolerability of these nervous system symptoms [See Dosage and Administration (2) ] .
Analysis of long-term data from Study 006, (median follow-up 180 weeks, 102 weeks, and 76 weeks for subjects treated with efavirenz + zidovudine + lamivudine, efavirenz + indinavir, and indinavir + zidovudine + lamivudine, respectively) showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among efavirenz-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 Emtricitabine and tenofovir are principally eliminated by the kidney; however, efavirenz is not.
Since ATRIPLA is a combination product and the dose of the individual components cannot be altered, patients with creatinine clearance <50 mL/min should not receive ATRIPLA.
Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir DF [See Adverse Reactions (6.3) ].
It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with ATRIPLA.
Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment, including patients who have previously experienced renal events while receiving HEPSERA.
ATRIPLA should be avoided with concurrent or recent use of a nephrotoxic agent.
5.8 Reproductive Risk Potential Pregnancy Category D: Efavirenz may cause fetal harm when administered during the first trimester to a pregnant woman.
Pregnancy should be avoided in women receiving ATRIPLA.
Barrier contraception must always be used in combination with other methods of contraception (e.g., oral or other hormonal contraceptives).
Because of the long half-life of efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation of ATRIPLA is recommended.
Women of childbearing potential should undergo pregnancy testing before initiation of ATRIPLA.
If this drug is used during the first trimester of pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus.
There are no adequate and well-controlled studies of ATRIPLA in pregnant women.
ATRIPLA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus, such as in pregnant women without other therapeutic options.
Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women, an Antiretroviral Pregnancy Registry has been established.
Physicians are encouraged to register patients who become pregnant by calling (800) 258-4263.
Efavirenz: As of July 2008, the Antiretroviral Pregnancy Registry has received prospective reports of 526 pregnancies exposed to efavirenz-containing regimens, nearly all of which were first-trimester exposures (507 pregnancies).
Birth defects occurred in 13 of 407 live births (first-trimester exposure) and 2 of 37 live births (second/third-trimester exposure).
One of these prospectively reported defects with first-trimester exposure was a neural tube defect.
A single case of anophthalmia with first-trimester exposure to efavirenz has also been prospectively reported; however, this case included severe oblique facial clefts and amniotic banding, a known association with anophthalmia.
There have been five retrospective reports of findings consistent with neural tube defects, including meningomyelocele.
All mothers were exposed to efavirenz-containing regimens in the first trimester.
Although a causal relationship of these events to the use of efavirenz has not been established, similar defects have been observed in preclinical studies of efavirenz.
Malformations have been observed in 3 of 20 fetuses/infants from efavirenz-treated cynomolgus monkeys (versus 0 of 20 concomitant controls) in a developmental toxicity study.
The pregnant monkeys were dosed throughout pregnancy (postcoital days 20–150) with efavirenz 60 mg/kg daily, a dose which resulted in plasma drug concentrations similar to those in humans given 600 mg/day of efavirenz.
Anencephaly and unilateral anophthalmia were observed in one fetus, microophthalmia was observed in another fetus, and cleft palate was observed in a third fetus.
Efavirenz crosses the placenta in cynomolgus monkeys and produces fetal blood concentrations similar to maternal blood concentrations.
Efavirenz has been shown to cross the placenta in rats and rabbits and produces fetal blood concentrations of efavirenz similar to maternal concentrations.
An increase in fetal resorptions was observed in rats at efavirenz doses that produced peak plasma concentrations and AUC values in female rats equivalent to or lower than those achieved in humans given 600 mg once daily of efavirenz.
Efavirenz produced no reproductive toxicities when given to pregnant rabbits at doses that produced peak plasma concentrations similar to and AUC values approximately half of those achieved in humans given 600 mg once daily of efavirenz.
5.9 Rash In controlled clinical trials, 26% (266/1008) of subjects treated with 600 mg efavirenz experienced new-onset skin rash compared with 17% (111/635) of subjects treated in control groups.
Rash associated with blistering, moist desquamation, or ulceration occurred in 0.9% (9/1008) of subjects treated with efavirenz.
The incidence of Grade 4 rash (e.g., erythema multiforme, Stevens-Johnson syndrome) in subjects treated with efavirenz 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 efavirenz (median time to onset of rash in adults was 11 days) and, in most subjects continuing therapy with efavirenz, rash resolves within 1 month (median duration, 16 days).
The discontinuation rate for rash in clinical trials was 1.7% (17/1008).
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.
Experience with efavirenz 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 efavirenz.
Nine of these subjects developed mild-to-moderate rash while receiving therapy with efavirenz, and two of these subjects discontinued because of rash.
5.10 Liver Enzymes In patients with known or suspected history of hepatitis B or C infection and in patients treated with other medications associated with liver toxicity, monitoring of liver enzymes is recommended [See also Warnings and Precautions (5.2) ].
In patients with persistent elevations of serum transaminases to greater than five times the upper limit of the normal range, the benefit of continued therapy with ATRIPLA needs to be weighed against the unknown risks of significant liver toxicity [See Adverse Reactions (6.2) ] .
5.11 Decreases in Bone Mineral Density Bone mineral density (BMD) monitoring should be considered for HIV-1 infected subjects who have a history of pathologic bone fracture or are at risk for osteopenia.
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.
In a 144-week study of treatment-naive subjects receiving tenofovir DF, decreases in BMD were seen at the lumbar spine and hip in both arms of the study.
At Week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving tenofovir DF + lamivudine + efavirenz compared with subjects receiving stavudine + lamivudine + efavirenz.
Changes in BMD at the hip were similar between the two treatment groups.
In both groups, the majority of the reduction in BMD occurred in the first 24–48 weeks of the study and this reduction was sustained through 144 weeks.
Twenty-eight percent of tenofovir DF-treated subjects vs.
21% of the comparator 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 tenofovir DF group and 6 subjects in the comparator group.
Tenofovir DF was associated with significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide, and urinary N-telopeptide), suggesting increased bone turnover.
Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving tenofovir DF.
The effects of tenofovir DF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown.
For additional information, consult the tenofovir DF prescribing information.
Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the use of tenofovir DF [See Adverse Reactions (6.3) ] .
5.12 Convulsions Convulsions have been observed in patients receiving efavirenz, generally in the presence of known medical history of seizures.
Caution must 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 (7.3) ].
5.13 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including the components of ATRIPLA.
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.
5.14 Fat Redistribution 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 antiretroviral therapy.
The mechanism and long-term consequences of these events are currently unknown.
A causal relationship has not been established.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION and FDA-APPROVED PATIENT LABELING 17.1 Drug Interactions A statement to patients and healthcare providers is included on the product’s bottle labels: ALERT: Find out about medicines that should NOT be taken with ATRIPLA.
ATRIPLA may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, nonprescription medication, or herbal products, particularly St.
17.2 Information for Patients Patients should be advised that: ATRIPLA is not a cure for HIV-1 infection and that they may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections.
Patients should remain under the care of a physician when using ATRIPLA.
The use of ATRIPLA has not been shown to reduce the risk of transmission of HIV-1 to others through sexual contact or blood contamination.
Patients should be advised to continue to practice safer sex and to use latex or polyurethane condoms to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions or blood.
Patients should be advised never to re-use or share needles.
The long term effects of ATRIPLA are unknown.
Redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known.
ATRIPLA should not be coadministered with SUSTIVA, EMTRIVA, VIREAD, or TRUVADA, or drugs containing lamivudine, including Combivir, Epivir, Epivir-HBV, Epzicom, or Trizivir.
ATRIPLA should not be administered with HEPSERA [See Warnings and Precautions (5.2) ] .
17.3 Lactic Acidosis/Severe Hepatomegaly with Steatosis Patients should be informed that lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported.
Treatment will be suspended in any patients who develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity (including nausea, vomiting, unusual or unexpected stomach discomfort, and weakness) [See Warnings and Precautions (5.1) ].
17.4 Patients Coinfected with HIV-1 and HBV Patients with HIV-1 should be tested for hepatitis B virus (HBV) before initiating antiretroviral therapy.
Patients should be advised that severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued EMTRIVA (emtricitabine) or VIREAD (tenofovir DF), which are components of ATRIPLA.
17.5 New Onset or Worsening Renal Impairment Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported.
ATRIPLA should be avoided with concurrent or recent use of a nephrotoxic agent [See Warnings and Precautions (5.7) ].
17.6 Decreases in Bone Mineral Density Patients should be informed that decreases in bone mineral density have been observed with the use of tenofovir DF.
Bone mineral density monitoring may be performed in patients who have a history of pathologic bone fracture or are at risk for osteopenia [See Warnings and Precautions (5.11) ] .
17.7 Dosing Instructions Patients should be advised to take ATRIPLA orally on an empty stomach and that it is important to take ATRIPLA on a regular dosing schedule to avoid missing doses.
17.8 Nervous System Symptoms Patients should be informed that central nervous system symptoms (NSS) including dizziness, insomnia, impaired concentration, drowsiness, and abnormal dreams are commonly reported during the first weeks of therapy with efavirenz.
Dosing at bedtime may improve the tolerability of these symptoms, which are likely to improve with continued therapy.
Patients should be alerted to the potential for additive effects when ATRIPLA is used concomitantly with alcohol or psychoactive drugs.
Patients should be instructed that if they experience NSS they should avoid potentially hazardous tasks such as driving or operating machinery [See Warnings and Precautions (5.6) , and Dosage and Administration (2) ].
17.9 Psychiatric Symptoms Patients should be informed that serious psychiatric symptoms including severe depression, suicide attempts, aggressive behavior, delusions, paranoia, and psychosis-like symptoms have been reported in patients receiving efavirenz.
If they experience severe psychiatric adverse experiences they should seek immediate medical evaluation.
Patients should be advised to inform their physician of any history of mental illness or substance abuse [See Warnings and Precautions (5.5) ].
17.10 Rash Patients should be informed that a common side effect is rash.
Rashes usually go away without any change in treatment.
However, since rash may be serious, patients should be advised to contact their physician promptly if rash occurs.
17.11 Reproductive Risk Potential Women receiving ATRIPLA should be instructed to avoid pregnancy [See Warnings and Precautions (5.8) ] .
A reliable form of barrier contraception must always be used in combination with other methods of contraception, including oral or other hormonal contraception.
Because of the long half-life of efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation of ATRIPLA is recommended.
Women should be advised to notify their physician if they become pregnant or plan to become pregnant while taking ATRIPLA.
If this drug is used during the first trimester of pregnancy, or if the patient becomes pregnant while taking this drug, she should be apprised of the potential harm to the fetus.
DOSAGE AND ADMINISTRATION
Recommended dose: One tablet once daily taken orally on an empty stomach, preferably at bedtime.
( 2 ) Dose in renal impairment: Should not be administered in patients with creatinine clearance <50 mL/min.
( 2 ) Adults: The dose of ATRIPLA is one tablet once daily taken orally on an empty stomach.
Dosing at bedtime may improve the tolerability of nervous system symptoms.
Pediatrics: ATRIPLA is not recommended for use in patients <18 years of age.
Renal Impairment: Because ATRIPLA is a fixed-dose combination, it should not be prescribed for patients requiring dosage adjustment such as those with moderate or severe renal impairment (creatinine clearance <50 mL/min).