Advertisement
Advertisement


News

FDA Approval Notice for Vitekta (Elvitegravir)

September 25, 2014

On September 24, 2014, FDA approved Vitekta (elvitegravir) 85 mg and 150 mg tablets. Vitekta is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor indicated in combination with an HIV protease inhibitor coadministered with ritonavir and with other antiretroviral drug(s) for the treatment of HIV-1 infection in antiretroviral treatment-experienced adults.


Dosing and Administration

Vitekta must be administered once daily with food in combination with a protease inhibitor coadministered with ritonavir and another antiretroviral drug. The protease inhibitor and ritonavir dosing regimens presented in the Table 1 below are the recommended regimens for use with Vitekta. For additional dosing instructions for these protease inhibitors and other concomitant antiretroviral drugs, refer to their respective prescribing information.

Table 1 Recommended Regimens*

Dosage of VitektaDosage of Concomitant Protease InhibitorDosage of Concomitant Ritonavir
85 mg orally once dailyAtazanavir 300 mg orally once daily100 mg orally once daily
Lopinavir 400 mg orally twice daily100 mg orally twice daily
150 mg orally once dailyDarunavir 600 mg orally twice daily100 mg orally twice daily
Fosamprenavir 700 mg orally twice daily100 mg orally twice daily
Tipranavir 500 mg orally twice daily200 mg orally twice daily

* Vitekta in combination with a protease inhibitor and ritonavir must be coadministered with another antiretroviral drug.

No dose adjustment of Vitekta is required for patients with renal impairment.

No dose adjustment of Vitekta is required in patients with mild (Child-Pugh Class A) or moderate hepatic impairment. Vitekta has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, Vitekta is not recommended for use in patients with severe hepatic impairment.


Data to Support Approval

The data to support the approval of Vitekta was from a phase 3 trial, (Study 145) in treatment-experienced adult patients with HIV-1 infection in which 712 HIV-1 infected, antiretroviral treatment-experienced adults received Vitekta (N=354) or raltegravir (N=358), each administered with a background regimen consisting of a fully active protease inhibitor coadministered with ritonavir and with other antiretroviral drug(s) for at least 96 weeks. [See clinical studies section below for details.]


Adverse Reactions

The proportion of subjects who discontinued study treatment due to adverse events, regardless of severity, was 3% in the Vitekta group and 4% in the raltegravir group. The most common adverse reaction (all Grades, incidence greater than or equal to 5%) in subjects receiving Vitekta in Study 145 was diarrhea. The most commonly reported adverse reactions (all grade) for Vitekta and raltegravir containing regimens, respectively were diarrhea (7% vs 5%), nausea (4% vs 3%) and headache (3% each).

The following limitations of use were included in section 1: Indications and Usage:

  • There are no comparative pharmacokinetic or clinical data evaluating Vitekta with cobicistat as single entities compared to STRIBILD®.
  • Vitekta coadministered with protease inhibitors and cobicistat is not recommended.
  • Coadministration of Vitekta with dosage regimens or HIV-1 protease inhibitors other than those presented in Table 1 is not recommended.


Contraindications

There are no contraindications to Vitekta.

Due to the need to use Vitekta with a protease inhibitor coadministered with ritonavir, consult prescribing information of coadministered protease inhibitor and ritonavir for their contraindications.


Warnings and Precautions

A highlight of the warnings and precautions are as follows:

  • Do not use with protease inhibitors coadministered with cobicistat. (5.2)
  • Do not use with other elvitegravir-containing drugs, including STRIBILD.


Drug Interactions

Elvitegravir is metabolized by CYP3A. Drugs that induce CYP3A activity are expected to increase the clearance of elvitegravir, as well as ritonavir. This may result in decreased plasma concentrations of elvitegravir and/or a concomitantly administered protease inhibitor and lead to loss of therapeutic effect and to possible resistance. The table below provides dosing recommendations as a result of potentially clinically significant drug interactions with Vitekta.a

Concomitant Drug Class: Drug NameEffect on ConcentrationbClinical Comment
Antiretroviral Agents: Protease Inhibitors (PIs)c
Atazanavir*↔ atazanavir
↑ elvitegravir
Atazanavir/ritonavir has been shown to significantly increase the plasma concentrations of Vitekta. There are no data available to make dosing recommendations for coadministration with doses of atazanavir/ritonavir other than 300/100 mg once daily. Please refer to Section 2 for dosage adjustments.
Lopinavir/ritonavir*↔ lopinavir
↑ elvitegravir
Lopinavir/ritonavir has been shown to significantly increase the plasma concentrations of elvitegravir. There are no data available to make dosing recommendations for coadministration with doses of lopinavir/ritonavir other than 400/100 mg twice daily. Please refer to Section 2 for dosage adjustments.
Other Protease Inhibitors (with or without ritonavir)Effect is unknownThere are no data available to make dosing recommendations for coadministration with protease inhibitors other than atazanavir, lopinavir/ritonavir, darunavir, fosamprenavir, and tipranavir.
Antiretroviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Didanosine*↔ didanosine
↔ elvitegravir
As didanosine is administered on an empty stomach, administer didanosine at least 1 hour before or 2 hours after Vitekta (which is administered with food).
Antiretroviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz↓ elvitegravirCoadministration of efavirenz and Vitekta is expected to decrease elvitegravir plasma concentration which may result in loss of therapeutic effect and in development of resistance. Such coadministration is not recommended.
Nevirapine↓ elvitegravirCoadministration of nevirapine and Vitekta is expected to decrease elvitegravir plasma concentration, which may result in loss of therapeutic effect and development of resistance. Such coadministration is not recommended.
Other Agents:
Acid Reducing Agents:
antacids*
↓ elvitegravirElvitegravir plasma concentrations are lower with antacids due to the formation of ionic complexes in the GI tract and not due to changes in gastric pH. It is recommended to separate Vitekta and antacid administration by at least 2 hours.
Anticonvulsants:
carbamazepine
oxcarbazepine phenobarbital
phenytoin
↓ elvitegravirCoadministration of phenobarbital, phenytoin, carbamazepine, or oxcarbazepine (CYP3A inducers) with Vitekta may decrease elvitegravir plasma concentrations, which may result in loss of therapeutic effect and in development of resistance. Alternative anticonvulsants should be considered.
Antifungals:
ketoconazole*
↑ elvitegravir
↑ ketoconazole
No dose adjustment of Vitekta is required when coadministered with ketoconazole.
Concentrations of ketoconazole may increase when used concomitantly with Vitekta in combination with protease inhibitors/ritonavir; the maximum daily dose of ketoconazole should not exceed 200 mg per day. Consult the prescribing information of coadministered protease inhibitors for any additional dosing recommendation for ketoconazole.
Antimycobacterials:
rifampin
rifapentine

rifabutin*
↓ elvitegravirCoadministration of rifampin or rifapentine, both potent CYP3A inducers, with Vitekta may lead to decreased elvitegravir exposures, which may result in loss of therapeutic effect and in development of resistance. Coadministration is not recommended.
↑ rifabutin
↑ 25-O-desacetylrifabutin
↓ elvitegravir
When rifabutin, a potent CYP3A inducer, is used concomitantly with Vitekta in combination with a protease inhibitor/ritonavir, dose reduction of rifabutin by at least 75% of the usual dose of 300 mg/day (eg, 150 mg every other day or 3 times per week) is recommended. Increased monitoring for rifabutin-associated adverse events is warranted. Consult the prescribing information of coadministered protease inhibitors for any additional dosing recommendation for rifabutin.
No dose adjustment of Vitekta is required when coadministered with the reduced dose of rifabutin.
Systemic Corticosteroids:
dexamethasone
↓ elvitegravirSystemic dexamethasone, a CYP3A inducer, may decrease elvitegravir plasma concentrations, which may result in loss of therapeutic effect and development of resistance. Alternative corticosteroids should be considered.
Endothelin Receptor Antagonists:
bosentan
↑ bosentan
↓ elvitegravir
Coadministration of bosentan in patients on Vitekta:
In patients who have been receiving Vitekta for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Coadministration of Vitekta in patients on bosentan:
Discontinue use of bosentan at least 36 hours prior to initiation of Vitekta. After at least 10 days following the initiation of Vitekta, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HCV Protease Inhibitors:

boceprevir
telaprevir
↓ boceprevir
↓ telaprevir
↑ or ↓ HIV protease inhibitors
Coadministration of boceprevir or telaprevir with HIV protease inhibitors/ritonavir resulted in reduced plasma concentrations of the HCV medication, and may increase or decrease the plasma concentrations of the protease inhibitor. This may result in loss of therapeutic effect and in development of resistance. Because Vitekta must be administered with a protease inhibitor/ritonavir, coadministration with telaprevir or boceprevir is not recommended.
Herbal Products:
St. John's wort (Hypericum perforatum)
↓ elvitegravirCoadministration of St. John's wort, a potent CYP3A inducer, may decrease elvitegravir plasma concentrations, which may result in loss of therapeutic effect and in development of resistance.
Coadministration of Vitekta with St. John's wort is not recommended.
Hormonal Contraceptives:
norgestimate/ethinyl estradiol
↑ norgestimate
↓ ethinyl estradiol
↔ elvitegravir
Plasma concentration of ethinyl estradiol may be decreased when used concomitantly with Vitekta in combination with a protease inhibitor/ritonavir. Alternative methods of non-hormonal contraception are recommended.
* Indicates that a drug-drug interaction trial was conducted.
a This table is not all inclusive.
b ↑ = Increase, ↓ = Decrease, ↔ = No change
c Protease inhibitors were coadministered with ritonavir.

Based on drug interaction studies conducted with elvitegravir, no clinically significant drug interactions have been either observed or expected when elvitegravir is combined with the following drugs: abacavir, darunavir, emtricitabine, etravirine, fosamprenavir, maraviroc, stavudine, tipranavir, tenofovir disoproxil fumarate, zidovudine; H2-receptor antagonists such as famotidine; proton-pump inhibitors such as omeprazole; and the HMG-CoA reductase inhibitors atorvastatin, pravastatin, and rosuvastatin.


Clinical Studies

The efficacy of Vitekta in treatment-experienced adult patients with HIV-1 infection is based on the analyses through 96 weeks from one randomized, double-blind, active-controlled trial, Study 145, in treatment-experienced, HIV-1 infected subjects (N=702). In Study 145, subjects were randomized in a 1:1 ratio to receive either Vitekta (150 mg or 85 mg) once daily or raltegravir 400 mg twice daily, each administered with a background regimen (BR) containing a fully active protease inhibitor coadministered with ritonavir and a second antiretroviral drug. The BR was selected by the investigator based on genotypic/phenotypic resistance testing and prior antiretroviral treatment history.

Virologic outcomes were similar across the treatment arms through 96 weeks as presented in the table below. The mean increase from baseline in CD4+ cell count at Week 96 was 205 cells/mm3 in Vitekta-treated subjects and 198 cells/mm3 in raltegravir-treated subjects.

Virologic Outcomes of Randomized Treatment of Study 145 in HIV-1 Infected Treatment-Experienced Adults (Week 96a Analysis)

 Vitekta + protease inhibitor/ritonavir + another antiretroviral drug
(N=351)
Raltegravir + protease inhibitor/ritonavir+ another antiretroviral drug
(N=351)
HIV-1 RNA <50 copies/mLb52%53%
HIV-1 RNA >50 copies/mLc36%31%
No Virologic Data at Week 9612%16%
Discontinued Study Drug Due to AE or Deathd3%7%
Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA <50 copies/mLe8%9%
Missing Data During Window but on Study Drug1%1%

a The Week 96 analysis window is between Day 645 and 700 (inclusive).
b Difference (95% CI) of response rate is -0.5% (-7.9%, 6.8%) at Week 96.
c Includes subjects who had >50 copies/mL in the Week 96 window; subjects who discontinued early due to lack or loss of efficacy; subjects who had a viral load >50 copies/mL at the time of change in background regimen; subjects who discontinued for reasons other than an adverse event, death, or lack or loss of efficacy, and at the time of discontinuation had a viral value of >50 copies/mL.
d Includes subjects who discontinued due to adverse event or death at any time point from Day 1 through the time window, if this resulted in no virologic data on treatment during the specified window.
e Includes subjects who discontinued for reasons other than an adverse event, death, or lack or loss of efficacy; eg., withdrew consent, loss to follow-up, etc.

Labeling for Vitekta will be posted soon at Drugs@FDA.

Vitekta is a product of Gilead Sciences, Foster City, CA.





This article was provided by U.S. Food and Drug Administration. Visit the FDA's website to find out more about their activities and publications.
 

No comments have been made.
 

Add Your Comment:
(Please note: Your name and comment will be public, and may even show up in
Internet search results. Be careful when providing personal information! Before
adding your comment, please read TheBody.com's Comment Policy.)

Your Name:


Your Location:

(ex: San Francisco, CA)

Your Comment:

Characters remaining:

Advertisement

The content on this page is free of advertiser influence and was produced by our editorial team. See our content and advertising policies.