December 15, 2011
Gilead Sciences Submits Supplemental New Drug Application to U.S. Food and Drug Administration for Truvada® for Reducing the Risk of Acquiring HIV
– If Approved, Product Would Represent First Antiretroviral Indicated to Reduce Risk of HIV Infection in Adults –
If the sNDA is approved, Truvada would be the first agent indicated for uninfected individuals to reduce the risk of acquiring HIV through sex, a prevention approach called PrEP. The sNDA is based on the results of two large placebo-controlled trials of Truvada as PrEP, sponsored by the
“The data from these large-scale clinical trials suggest that Truvada may have a role to play in meeting the urgent public health need to reduce new HIV infections,” said
According to current
Truvada is not currently indicated to reduce the risk of HIV infection.
The first trial providing data to support the Truvada sNDA is a Phase 3 randomized, double-blind, placebo-controlled trial known as the Pre-Exposure Prophylaxis Initiative (iPrEx), which was sponsored by the NIH and conducted among 2,499 high-risk HIV-negative adult men who have sex with men in
“It is clear that new prevention strategies are urgently needed to tackle the unacceptably high number of new HIV infections in the
The Truvada sNDA submission is also supported by data from Partners PrEP, a Phase 3 randomized, double-blind, placebo-controlled trial conducted among 4,758 heterosexual couples in
“This year marked the 30-year milestone of the AIDS pandemic and the loss of an estimated 30 million lives, but it has also been a year of hope with several significant new advances in antiretroviral-based HIV prevention,” said
Additional supportive data come from two studies sponsored by CDC. The first trial, known as TDF2, was a Phase 3 randomized, double-blind, placebo-controlled trial conducted in
Although full details are not yet available, another separate Phase 3 study of Truvada for PrEP known as FEM-PrEP was stopped in
In all studies, side effects included nausea, weight loss and serum creatinine elevations. The incidence of side effects was consistent with Truvada’s safety and tolerability profile when used as HIV treatment, which is supported by more than 1.8 million years of patient use. Overall, there have been more than 4.4 million patient years of experience with tenofovir-containing regimens. Three cases of resistance to emtricitabine were reported in the iPrEx trial among participants who tested negative for HIV infection by serology at enrollment, but were later found to have been infected with HIV prior to enrollment using a different assay. Two of these cases occurred in the active drug arm, and one case occurred in the placebo arm.
Based on the iPrEx trial results, in
CDC guidance also stresses that effectiveness is highly dependent on medication adherence; the importance of confirming that patients who take Truvada for PrEP are at substantial ongoing risk for HIV infection; the need to provide counseling on the importance of adhering closely to the prescribed regimen and using other HIV prevention methods; and the importance of regularly testing for HIV infection.
CDC is currently developing formal U.S. Public Health Service guidelines for the use of PrEP. Among the topics that will be addressed by the formal guidelines are procedures for initial HIV testing and health screening, as well as ongoing monitoring for side effects, clinical toxicities, HIV infection and possible drug resistance among those who become infected despite taking PrEP.
Gilead donated drug and placebo tablets for iPrEx, Partners PrEP, TDF2 and CDC 4323, as well as for other ongoing trials of PrEP for HIV prevention being conducted worldwide among multiple high-risk populations.
Important Safety Product Information About Truvada, Including Boxed Warnings
Truvada, a combination of Emtriva® (emtricitabine) and Viread® (tenofovir disoproxil fumarate [DF]), is indicated in combination with other antiretroviral agents (such as non-nucleoside reverse transcriptase inhibitors or protease inhibitors) for the treatment of HIV-1 infection.
The following points should be considered when initiating therapy with Truvada for the treatment of HIV-1 infection:
- It is not recommended that Truvada be used as a component of a triple nucleoside regimen.
- Truvada should not be coadministered with Atripla® (efavirenz/emtricitabine/tenofovir DF), Emtriva, Viread, or lamivudine-containing products.
- In treatment-experienced patients, the use of Truvada should be guided by laboratory testing and treatment history.
WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including Viread, a component of Truvada, in combination with other antiretrovirals.
Truvada is not approved for the treatment of chronic hepatitis B virus (HBV) infection, and the safety and efficacy of Truvada 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 Truvada. 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 Truvada. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
WARNINGS AND PRECAUTIONS
New Onset or Worsening Renal Impairment
- Emtricitabine and tenofovir are principally eliminated by the kidney. Renal impairment, including acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir DF.
- Assess CrCl before initiating treatment with Truvada. Routinely monitor CrCl and serum phosphorus in patients at risk for renal impairment, including patients who have previously experienced renal events while receiving Hepsera® (adefovir dipivoxil).
- Dosing interval adjustment of Truvada and close monitoring of renal function are recommended in all patients with CrCl 30–49 mL/min. No safety or efficacy data are available in patients with renal impairment who received Truvada using these dosing guidelines, so the potential benefit of Truvada therapy should be assessed against the potential risk of renal toxicity. Truvada should not be administered in patients with CrCl <30 mL/min or patients requiring hemodialysis.
- Avoid administering Truvada with concurrent or recent use of nephrotoxic drugs.
Coadministration With Other Products
- Since Truvada contains emtricitabine and tenofovir DF, Truvada should not be coadministered with Atripla, Emtriva or Viread. Due to similarities between emtricitabine and lamivudine, Truvada should not be coadministered with other drugs containing lamivudine, including Combivir (zidovudine/lamivudine) Epivir or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), or Trizivir (abacavir sulfate/lamivudine/zidovudine).
- Truvada should not be administered with Hepsera.
Bone Mineral Density
- Decreases in bone mineral density (BMD): BMD monitoring should be considered for HIV-1 infected patients who have a history of pathologic bone fracture or who are at risk for osteopenia. Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the use of Viread.
- 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.
- Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Truvada, which may necessitate further evaluation and treatment.
Early Virologic Failure
- Triple nucleoside-only regimens: Early virologic failure has been reported in HIV-infected patients on regimens containing only 3 nucleoside reverse transcriptase inhibitors (NRTIs). Monitor carefully and consider treatment modification.
- The most common (incidence ≥10%, any severity) and/or treatment-emergent (Grade 2–4, occurring in ≥5% of subjects) adverse reactions occurring in subjects treated with efavirenz, emtricitabine and tenofovir DF in Study 934 through 144 weeks include diarrhea, nausea, fatigue, sinusitis, upper respiratory tract infections, nasopharyngitis, headache, dizziness, depression, insomnia, abnormal dreams and rash.
- Didanosine (ddI): tenofovir disoproxil fumarate increases ddI concentrations. Use with caution and monitor for evidence of ddI toxicity (eg, pancreatitis, neuropathy) when coadministered. The ddI dose should be reduced to 250 mg for patients weighing >60 kg. Data are not available to recommend a dose adjustment of ddI for patients weighing <60 kg. Coadministration of didanosine buffered tablet formulation with Truvada should be under fasted conditions.
- Atazanavir (ATV): coadministration decreases ATV concentrations and increases tenofovir concentrations. ATV 300 mg should be boosted with ritonavir 100 mg only and taken with food when administered with Truvada. Monitor for evidence of tenofovir-associated adverse reactions and discontinue Truvada if appropriate. ATV without ritonavir should not be coadministered with Truvada.
- Lopinavir/ritonavir (LPV/r): coadministration increases tenofovir concentrations. Patients receiving LPV/r and Truvada should be monitored for tenofovir-associated adverse reactions and discontinue Truvada if appropriate.
DOSAGE AND ADMINISTRATION
- Recommended dose: one tablet (containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) once daily taken orally with or without food in adults and pediatric patients 12 years of age and older with body weight greater than or equal to 35 kg (greater than or equal to 77 lb.).
|Renal dosing guidelines|
|Creatinine clearance (mL/min)a||≥50||30-49||<30
(including patients requiring hemodialysis)
|Recommended dosing||Every 24 hours||Every 48 hours||Truvada should not be administered|
|aCalculated using ideal (lean) body weight.|
- The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated in patients with moderate renal impairment; clinical response to treatment and renal function should be closely monitored in these patients.
Please see full Prescribing Information for Truvada (including BOXED WARNINGS).
This press release includes forward-looking statements, within the meaning of the Private Securities Litigation Reform Act of 1995, that are subject to risks, uncertainties and other factors, including the risk that the
U.S. full prescribing information for Truvada is available at www.Truvada.com.
Truvada, Viread, Emtriva and Hepsera are registered trademarks of
Atripla is a registered trademark of
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Gilead Sciences, Inc.
Susan Hubbard, 650-522-5715 (Investors)
Cara Miller, 650-522-1616 (Media)