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Revised "Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents" become available today (October 29, 2004) on the AIDSinfo.nih.gov website.
What's New in the Document?
This guidelines revision represents a major rewriting of the document to improve its organization and readability. The tables are updated with the most current available information. The following major changes have been made to the March 28, 2004 version of the guidelines:
Changes in Recommendations:
When to start?
For asymptomatic treatment-naïve patients with CD4+ T cell count >350
cells/mm3, the viral load recommendation to defer or to consider therapy has
been increased from 55,000 to 100,000 copies/mL. This is based on more recent
data supporting HIV RNA level of >100,000 copies/mL being a stronger predictor
for disease progression than >55,000 copies/mL, though even at these CD4
and viral load levels, the risk of disease progression is still relatively low.
Most experienced clinicians will defer therapy with quarterly clinical and laboratory
evaluation.
What to start with?
. stavudine -- has been moved from "preferred" to "alternative"
due to increasing reports of stavudine-associated toxicities
. tenofovir + lamivudine (or emtricitabine) -- is now recommended as a
2-NRTI backbone for both NNRTI- and PI-based regimens. Previously, this recommendation
was limited to NNRTI-based regimens only.
. emtricitabine -- is now included as an option for part of a preferred
or alternative 2-NRTI backbone
Additions to the Guidelines Document:
Special Populations section -- discussions on special considerations for antiretroviral
therapy in the following patient populations are added to this document:
. HIV-infected adolescents
. Injection drug users
. Hepatitis B/HIV co-infected patients
. Hepatitis C/HIV co-infected patients
. HIV patients with tuberculosis
Discussion on Discontinuation or Interruption of Antiretroviral Therapy
Table 3a -- "Probability of progressing to AIDS or death according to CD4 cell
count, viral load, and sociodemographic factors" -- reproduced with permission
from Lancet 2002.
Table 3b -- "Predicted 6-month risk of AIDS according to age and current CD4
cell count and viral load, based on a Poisson regression model" -- reproduced
with permission from AIDS 2004.
Table 7 -- "A compilation of 48-week treatment outcome data from selected clinical
trials of combination antiretroviral therapy in treatment-naïve individuals"
Tables 16 a-c -- New tables on "Antiretroviral therapy associated adverse effects
and management recommendations"
Deletion from the Guidelines Document:
What not to use?
. Hydroxyurea -- Hydroxyurea has been removed from this list as it is the
opinion of the Panel that discussions in the guidelines should limit themselves
to commentary on FDA-approved agents that are indicated for the treatment of
HIV infection. Hydroxyurea, though used by some as adjunctive therapy to antiretroviral
agents, is not considered, by itself, an antiretroviral agent, and thus will
not be discussed in this guidelines document.
The most current version of this, and other national HIV-related guidelines
are always available at http://aidsinfo.nih.gov/
Return to index
In October, 2004, the Kaletra (lopinavir and ritonavir), Soft Gel Capsules and Oral Solution, labeling has been revised to include long-term (week 144-204) efficacy and safety results from two phase II trials. Specifically, the Week 204 efficacy results from study M97-720 in antiretroviral-naïve subjects and the Week 144 results from study M97-765 in antiretroviral-experienced subjects were included in the label. In addition, results of a multiple dose study in HIV and HCV co-infected subjects with mild to moderate hepatic impairment and Week 104 mice and rat data were submitted to update the respective sections of the package insert.
The following changes appear in the revised labeling.
CLINCIAL PHARMACOLOGY:
Information from a multiple dose study in HIV and HCV co-infected subjects with mild to moderate hepatic impairment was added. Specifically, the following text was included.
Multiple doses of KALETRA 400/100 mg bid to HIV and HCV co-infected subjects with mild to moderate hepatic impairment (n=12) resulted in a 30% increase in lopinavir AUC and 20% increase in Cmax compared to HIV-infected subjects with normal hepatic function (n=12). Additionally, the plasma protein binding of lopinavir was statistically significantly lower in both mild and moderate hepatic impairment compared to controls (99.09 vs 99.31%, respectively). Caution should be exercised when administering KALETRA to subjects with hepatic impairment. KALETRA has not been studied in patients with severe hepatic impairment.
Results from drug-drug interaction studies with fosamprenavir (Lexiva) and tenofovir (Viread) were included.
INDICATIONS AND USAGE and Description of Clinical Studies:
These sections were updated to include long-term efficacy results from two uncontrolled dose-ranging studies. Specifically the Week 204 efficacy results from study M97-720 in antiretroviral-naïve subjects and the Week 144 results from study M97-765 in antiretroviral-experienced subjects were included as follows:
Through 204 weeks of treatment in study 720, the proportion of patients with HIV RNA <400 (<50) copies/mL was 71% (70%) [n=100], and the corresponding mean increase in CD4 cell count was 440 cells/mm3. Twenty-eight patients (28%) discontinued the study, including 9 (9%) discontinuations due to adverse events and 1 (1%) death. Through 144 weeks of treatment in study 765, the proportion of patients with HIV RNA <400 (<50) copies/mL was 54% (50%) [n=70], and the corresponding mean increase in CD4 cell count was 212 cells/mm3. Twenty-seven patients (39%) discontinued the study, including 9 (13%) discontinuations secondary to adverse events and 2 (3%) deaths.
WARNINGS:
The erectile dysfunction drugs tadalafil (Cialis), and vardenafil (Levitra)
were included with sildenafil (Viagra) under Pharmacokinetics: Drug-Drug Interactions,
as follows:
Particular caution should be used when prescribing sildenafil, tadalafil, or
vardenafil in patients receiving KALETRA. Co-administration of KALETRA with
these drugs is expected to substantially increase their concentrations and may
result in an increase in associated adverse events including hypotension, syncope,
visual changes and prolonged erection (see PRECAUTIONS: Drug Interactions and
the complete prescribing information for sildenafil tadalafil, and vardenafil.)
PRECAUTIONS:
The following statement regarding immune reconstitution syndrome was added.
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination
antiretroviral therapy, including KALETRA. 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 carinii pneumonia,
or tuberculosis) which may necessitate further evaluation and treatment.
Drug Interactions
· Table 9: Established and
Other Potentially Significant Drug Interactions was updated to include information
with tenofovir, fosamprenavir, voriconazole, tadalafil, vardenafil and hormonal
contraceptives as follows.
o KALETRA increases tenofovir concentrations.
The mechanism of this interaction is unknown. Patients receiving KALETRA and
tenofovir should be monitored for tenofovir-associated adverse events
o An increased rate of adverse events has
been observed with coadministration with KALETRA and fosamprenavir. Appropriate
doses of the combinations with respect to safety and efficacy have not been
established.
o Coadministration of voriconazole (VFEND)
with KALETRA has not been studied. However, administration of voriconazole with
ritonavir 400 mg every 12 hours decreased voriconazole steady-state AUC by an
average of 82%. The effect of lower ritonavir doses on voriconazole is not known
at this time. Until data are available, voriconazole should not be administered
to patients receiving KALETRA
o Use tadalafil (Cialis) with caution at
reduced doses of 10 mg every 72 hours with increased monitoring for adverse
events
o Use vardenafil (Levitra) with caution
at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring
for adverse events
o Because contraceptive steroid concentrations
may be altered when KALETRA is coadministered with oral contraceptives or with
the contraceptive patch, alternative methods of nonhormonal contraception are
recommended.
Carcinogenesis, Mutagenesis and Impairment of Fertility
· Results from the long-term
carcinogenicity studies with KALETRA were included as follows.
o Long-term carcinogenicity studies of KALETRA
in animal systems have not been completed. Lopinavir/ritonavir combination was
evaluated for carcinogenic potential by oral gavage administration to mice and
rats for up to 104 weeks. Results showed an increase in the incidence of benign
hepatocellular adenomas and an increase in the combined incidence of
hepatocellular adenomas plus carcinoma in both males and females in mice and
males in rats at doses that produced approximately 1.6-2.2 times (mice) and
0.5 times (rats) the human exposure (based on AUC0-24hr measurement) at the
recommended dose of 400/100 mg KALETRA twice daily. Administration of lopinavir/ritonavir
did not cause a statistically significant increase in the incidence of any other
benign or malignant neoplasm in mice or rats. It is not known how predictive
the results of rodent carcinogenicity studies may be for humans. However, neither
lopinavir nor ritonavir was found to be mutagenic or clastogenic in a battery
of in vitro and in vivo assays including the Ames bacterial reverse mutation
assay using S. typhimurium and E. coli, the mouse lymphoma assay, the mouse
micronucleus test and chromosomal aberration
ADVERSE REACTIONS:
· Table 10 (Adverse Events)
and 11 (laboratory abnormalities) were updated to include the Week 204 data
from study M97-720 and the Week 144 data from study M97-7
· Stevens Johnson Syndrome and
erythema multiforme were added under Skin and Appendages to the postmarketing
experience Section.
FDA approved, on October 15, 2004, a supplemental new drug application for Fuzeon (enfuvirtide, also known as T-20) injection, in combination with other antiretroviral agents, for the treatment of HIV-1 infection in treatment experienced patients with ongoing viremia, granting "traditional approval."
FDA originally approved Fuzeon on March 13, 2003 under the regulations at 21 CFR 314, Subpart H, for accelerated approval of new drugs for serious or life-threatening illnesses. Approval of this supplement is based on fulfillment of research commitments made by the sponsor, Hoffmann-La Roche, Inc. of Nutley, NJ, under 21 CFR 314.510. The supplemental application submitted in support of traditional approval of enfuvirtide included 48 week safety and efficacy data from studies T20-301 and T20-302. These studies also provided the basis for the accelerated approval. In addition, safety data from clinical access studies, open label safety studies, the early access program, and pediatric studies were submitted in this supplemental application.
There was clear evidence of efficacy in the two randomized, controlled, 48 week trials in heavily pretreated HIV-infected subjects. In these studies, the primary efficacy endpoint was the maintenance or improvement of treatment effect from week 24 to week 48 as measured by the percentage of subjects with a HIV RNA level less than 50 copies/ml, HIV RNA less than 400 copies/ml, or a one log or more decrease in viral load. A greater proportion of subjects receiving enfuvirtide plus an optimized background (OB) antiretroviral regimen had a treatment response at 48 weeks compared to those receiving an OB regimen alone (p<0.001).
Review of the safety data submitted in this supplement did not identify any new or unexpected toxicities for enfuvirtide. As expected, injection site reactions (ISRs) were the most common adverse event and were reported by almost all subjects receiving enfuvirtide (98%). ISRs were common at the week one study visit (86%) and continued to occur throughout treatment. Most ISRs were associated with pain or discomfort, erythema, induration, and nodules or cysts. Infectious complications were rare (1.7%). ISRs and injection difficulties, such as inconvenience and injection fatigue, had a substantial impact on study participation and were the cause of early discontinuation in 7% of the study population. An increased incidence of pneumonia was observed in the first 24 weeks of the phase 3 studies and again in the second 24 weeks. There was no evidence of increasing risk over time, and no new risk factors or changes in severity of pneumonia were identified. Finally, episodes of systemic hypersensitivity, which were reported in less than 1% of subjects during the first 24 weeks of the phase 3 trials, were rare in the second 24 weeks of these studies and in the other studies included in this supplement. The observed toxicities did not outweigh the clear benefit of enfuvirtide as a treatment option for treatment experienced patients with measurable ongoing viremia.
The following changes were made to the package insert and patient package insert:
CLINICAL PHARMACOLOGY, Pediatric Patients
The pharmacokinetics of enfuvirtide (AUC, Cmax, Ctrough, and apparent clearance) were changed to reflect the results of additional subjects enrolled in studied T20-310. These results were similar to previous findings and did not change the dosing recommendation for pediatric patients.
INDICATIONS AND USAGE
This section was updated to provide the 48 week efficacy data from studies T20-301 and T20-302.
The outcome table (Table 3) was revised to provide clear information on the outcome for each subject in these studies.
Limited information on the efficacy of enfuvirtide in subgroup populations was added.
PRECAUTIONS, Pediatric Use
This section was revised to reflect the efficacy and safety results from additional subjects enrolled in study T20-310.
ADVERSE REACTIONS
Injection site reactions
The table summarizing individual signs and symptoms of injection site reactions was revised to decrease the number of footnotes and increase the comprehension of the results.
A brief description of the results of an ISR intervention study was added.
Other adverse events
Because of the difference in rate of exposure, adverse event results for subjects receiving enfuvirtide were provided as percentages and as rates per 100 patient-years.
PATIENT PACKAGE INSERT
Similar revisions were made to the patient package insert to improve readability and patient comprehension.
Accelerated approval recognizes improvement in a surrogate marker which is reasonably
likely to predict clinical benefit. The subsequent study under the commitments
made under the Accelerated Approval requirements demonstrated durable viral
suppression and safety for 48 weeks, upon which the traditional approval is
based.
Sustiva labeling has been revised to include safety and efficacy data representing 168 weeks of treatment from Study 006 ( efavirenz + lamivudine + zidovudine vs indinavir + lamivudine + zidovudine vs efavirenz + indinavir) and other available data.
The following changes appear in the revised labeling:
The Microbiology section was updated to include resistance information from
clinical studies and cross-resistance data.
The Clinical Pharmacology section was updated to include pharmacokinetic data
on the interaction between efavirenz and atazanavir/ritonavir and efavirenz
and voriconazole
The Description of Clinical Studies section was updated to efficacy data through
168 weeks of therapy from study 006. Study 006 was a randomized, open-label
trial, compared SUSTIVA (600 mg once daily) + zidovudine (300 mg twice daily)
+ lamivudine (150 mg twice daily) vs indinavir (800 mg every 8 hours) + zidovudine
(300 mg twice daily) + lamivudine (150 mg twice daily) vs SUSTIVA (600 mg once
daily) + indinavir (1000 mg every 8 hours). At week 168, the proportion of subjects
who achieved and maintained HIV RNA < 400 copies/mL (and < 50 copies/mL)
was the following
SUSTIVA + zidovudine + lamivudine = 48% (43%)
Indinavir + zidovudine + lamivudine = 29% (23%)
SUSTIVA + indinavir = 40% (31%)
The Contraindications section was updated to include the following:
SUSTIVA should not be administered concurrently with voriconazole because SUSTIVA
significantly decreases voriconazole plasma concentrations
The Warnings - Psychiatric Symptoms and Nervous System subsections were updated
as follows:
Psychiatric Symptoms: Serious psychiatric adverse experiences have been reported
in patients treated with SUSTIVA. In controlled trials of 1008 patients treated
with regimens containing SUSTIVA for a mean of 2.1 years and 635 patients treated
with control regimens for a mean of 1.5 years, the frequency of specific serious
psychiatric events among patients who received SUSTIVA 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 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 SUSTIVA and control treatment groups. In Study 006, onset
of new serious psychiatric symptoms occurred throughout the study for both SUSTIVA-treated
and control-treated patients. One percent of SUSTIVA-treated patients 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 SUSTIVA 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 SUSTIVA,
and if so, to determine whether the risks of continued therapy outweigh the
benefits.
Nervous System Symptoms: Analysis of long-term data from Study 006 (median follow-up 180 weeks, 102 weeks, and 76 weeks for patients treated with SUSTIVA + zidovudine + lamivudine, SUSTIVA + indinavir, and indinavir + zidovudine + lamivudine, respectively) showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among SUSTIVA-treated patients were generally similar to those in the indinavir-containing control arm.
The Precautions section was updated to include information on Immune Reconstitution Syndrome and update Table 5: Drugs That Should Not Be Coadministered with SUSTIVA and the Established Drug Interaction Table as follows:
Immune Reconstitution Syndrome: Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including SUSTIVA. 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 carinii pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.
Voriconazole was added to Table 5: Drugs That Should Not Be Coadministered
with SUSTIVA
The Established Drug Interaction table includes the following information regarding
atazanavir
When coadministered with SUSTIVA in treatment-naive patients, the recommended
dose of atazanavir is 300 mg with ritonavir 100 mg and SUSTIVA 600 mg (all once
daily). Dosing recommendations for SUSTIVA and atazanavir in treatment-experienced
patients have not been established.
The Adverse Reactions section was updated to include the 168 week safety data
(adverse reactions and laboratory abnormalities) from study 006
Table 9: Selected Grade 3 and 4 laboratory abnormality table was also updated
to include triglyceride data > 751 mg/dL from studies 006 and ACTG 364
The Liver Enzymes and Lipids subsection were revised to include the following
information from study 006
Liver function tests should be monitored in patients with a history of hepatitis B and/or C. In the long-term data set from Study 006, 137 patients treated with SUSTIVA-containing regimens (median duration of therapy, 68 weeks) and 84 treated with a control regimen (median duration, 56 weeks) were seropositive at screening for hepatitis B (surface antigen positive) and/or C (hepatitis C antibody positive). Among these co-infected patients, elevations in AST to greater than five times ULN developed in 13% of patients in the SUSTIVA arms and 7% of those in the control arm, and elevations in ALT to greater than five times ULN developed in 20% of patients in the SUSTIVA arms and 7% of patients in the control arm. Among co-infected patients, 3% of those treated with SUSTIVA-containing regimens and 2% in the control arm discontinued from the study because of liver or biliary system disorders
Lipids: Increases from baseline in total cholesterol of 10-20% have been observed in some uninfected volunteers receiving SUSTIVA. In patients treated with SUSTIVA + zidovudine + lamivudine, increases from baseline in nonfasting total cholesterol and HDL of approximately 20% and 25%, respectively, were observed. In patients treated with SUSTIVA + indinavir, increases from baseline in nonfasting cholesterol and HDL of approximately 40% and 35%, respectively, were observed. Nonfasting total cholesterol levels > 240 mg/dL and > 300 mg/dL were reported in 34% and 9%, respectively, of patients treated with SUSTIVA + zidovudine + lamivudine, 54% and 20%, respectively, of patients treated with SUSTIVA + indinavir, and 28% and 4%, respectively, of patients treated with indinavir + zidovudine + lamivudine. The effects of SUSTIVA on triglycerides and LDL were not well characterized since samples were taken from nonfasting patients. The clinical significance of these findings is unknown.
The complete revised label will be available soon at Drugs@FDA
The Food and Drug Administration, on August 3, 2004, approved Sculptra, an injectable filler to correct facial fat loss in people with human immunodeficiency virus (HIV).
Sculptra is the first such treatment approved for a condition known as lipoatrophy, or facial wasting, a sinking of the cheek, eye and temple areas of the face caused by the loss of fat tissue under the skin which can affect HIV patients. FDA expedited review of the product because of its importance in treating people living with AIDS.
Sculptra is an injectable form of poly-L-lactic acid, a biodegradable, biocompatible synthetic polymer from the alpha-hydroxy-acid family that has been widely used for many years in dissolvable stitches, bone screws and facial implants.
FDA approval of Sculptra was based on data from four studies, totaling 277 HIV-positive patients with severe facial lipoatrophy. The patients, who were all being treated with antiretroviral drugs, were primarily white males, mostly ages 41 to 45. Patients were given three to six injections of Sculptra at two-week intervals and were followed for two years.
Skin thickness measurements and serial photographs from clinical studies were assessed, as well as other data submitted by the manufacturer, Dermik Laboratories, of Berwyn, Pa. Analysis indicated that the product significantly improved facial appearance, and was safe for restoration and/or correction of shape and contour deficiencies resulting from facial fat loss in patients with HIV/AIDS. Sculptra was shown to produce significant increases in dermal thickness (up to 2 to 3 times baseline values), adding volume to facial tissue and restoring shape to areas of the face with fat loss.
After an initial treatment series, repeat treatments may be needed to maintain the correction.
Most adverse events were related to the injection itself and included nodules, redness, swelling and bruising in the injection area.
The studies also demonstrated significant improvement in quality of life, and measures of anxiety and depression, conditions which can be associated with lipoatrophy.
Sculptra should only be used in patients with HIV by health care providers
who are fully familiar with the product training materials provided by Dermik
and the entire product package insert. The use of the product for other indications,
such as to treat wrinkles, has not been approved by FDA.
Sculptra should not be used in anyone who is allergic to any of the product's
components.
As a condition of approval, Dermik has agreed to conduct an open-label registry
study of 100 patients for five years to evaluate Sculptra's long-term safety.
The study will include at least 30 females and 30 people with dark skin types.
FDA announced approval on August 2, 2004 of two fixed-dose combination (FDC) antiretroviral drug products for use with other antiretroviral agents for the treatment of HIV-1 infection. The FDCs are GlaxoSmithKline's EPZICOM(tm) (abacavir/lamivudine) and Gilead Sciences, Inc.'s TRUVADA(tm) (tenofovir disoproxil/emtricitabine)
These FDC approvals are important because they provide simplified dosing regimens
- one pill, once daily, for the component of multi-drug therapy represented
by these FDCs.
TRUVADA(tm) (tenofovir disoproxil/emtricitabine) - Gilead Sciences, Inc.
TRUVADA is a fixed-dose combination (FDC) of the antiretroviral drugs tenofovir disoproxil fumarate 300 mg (TDF) and emtricitabine 200 mg (FTC), both of which are approved individually under the brand names of VIREAD(tm) (tenofovir disoproxil fumarate) and EMTRIVA(tm) (emtricitabine).
The approval of TRUVADA is based on bioequivalence studies demonstrating similar pharmacokinetic parameters of the combination product and the individual products, safety and efficacy data that exist for both components individually, and efficacy results from studies using the combination of TDF and lamivudine (3TC), [lamivudine is an approved product with many similarities to FTC] are being extrapolated to support the use of the TDF/FTC combination.
TRUVADA should be considered as an alternative to TDF and 3TC for treatment
naïve patients who might benefit from a once-a-day regimen.
EPZICOM(tm) (abacavir/lamivudine) - GlaxoSmithKline
EPZICOM is a fixed dose combination (FDC) of the antiretroviral drugs abacavir sulfate 600 mg and lamivudine 300 mg, both of which are approved individually under the brand names of ZIAGEN(tm) (abacavir sulfate) and EPIVIR(tm) (lamivudine).
EPZICOM is being approved based on a large well-controlled clinical study which
showed that abacavir dosed once daily had similar antiviral effect as abacavir
dosed twice daily both in conjunction with lamivudine and efaviranz.
The important safety issue regarding abacavir-containing products, including
EPZICOM, is abacavir hypersensitivity reaction (a serious allergic reaction).
Previous clinical trials showed that there is a possibility of this hypersensitivity
reaction occurring in approximately 8% of the patients. EPZICOM should be discontinued
a soon as a hypersensitivity reaction is suspected. EPZICOM or other abacavir-containing
products must not be restarted following a hypersensitivity reaction because
more severe symptoms can occur within hours and may include life-threatening
hypotension and death. Information on this serious allergic reaction has been
updated in the EPZICOM package insert as well as the patient Medguide/Warning
Card.
Return to Index
On July 6, 2004, the FDA Division of Antiviral Drug Products approved a new dosing regimen for REYATAZ. In antiretroviral-experienced patients the new recommended dose is:
REYATAZ 300 mg (two 150 mg capsules) once daily plus ritonavir 100 mg once daily taken taken with food.
For antiretroviral-naïve patients the recommended dose remains as REYATAZ 400 mg (two 200 mg capsules) once daily with food.
The data to support the new dosing regimen came from study AI424-045, a study of patients who had failed at least two regimens containing medications from the three ARV drug classes available at the time of enrollment. This 48-week trial evaluated the efficacy and safety of REYATAZ 300 mg + ritonavir 100 mg once daily or REYATAZ 400 mg + saquinavir 1200 mg once daily compared to lopinavir/ritonavir 400/100 mg twice daily each with tenofovir and an nucleocide reverse transcriptase inhibitor (NRTI).
REYATAZ/ritonavir and lopinavir/ritonavir were similar for the primary efficacy outcome measure of time-averaged difference in change from baseline in HIV RNA level. The HIV RNA change from baseline was -1.58 log10 copies/mL for REYATAZ/ritonavir and -1.70 log10 copies/mL for lopinavir/ritonavir.
Study AI424-045 was not large enough to reach a definitive conclusion that REYATAZ/ritonavir and lopinavir/ritonavir are equivalent on the secondary efficacy outcome measures of proportion below the HIV RNA lower limit of detection. The proportion of patients with HIV RNA < 400 copies/mL and < 50 copies/mL at week 48 was 55% and 38% for REYATAZ/ritonavir and 57% and 45% for lopinavir/ritonavir, respectively.
The major revisions to the package insert are summarized below.
INDICATIONS AND USAGE:
Information that should be considered when initiating therapy with REYATAZ was added as follows. This data pertains to REYATAZ/ritonavir.
The following points should be considered when initiating therapy with REYATAZ:
In antiretroviral-experienced patients with prior virologic failure, coadministration of REYATAZ with ritonavir is recommended.
In Study AI424-045 REYATAZ/ritonavir and lopinavir/ritonavir were similar for the primary efficacy outcome measure of time-averaged difference in change from baseline in HIV RNA level. This study was not large enough to reach a definitive conclusion that REYATAZ/ritonavir and lopinavir/ritonavir are equivalent on the secondary efficacy outcome measure of proportions below the HIV RNA lower limit of detection. (See Description of Clinical Studies)
The number of baseline primary protease inhibitor mutations affects the virologic
response of REYATAZ/ritonavir (See CLINICAL PHARMACOLOGY: Microbiology)
There are no data regarding the use of REYATAZ/ritonavir in therapy-naive patients.
CLINICAL PHARMACOLOGY
Microbiology
A table was included to provide information regarding HIV RNA response at week 48 by number and type of baseline protease inhibitor mutations and baseline phenotype in treatment-experienced subjects (study AI424-045). In summary, HIV RNA the response rate (< 400 copies/mL) was 75% for both REYATAZ/ritonavir (50/67) and lopinavir/ritonavir (50/67) in patients with 0-2 baseline primary protease inhibitor mutations. In patients with 3-4 baseline primary protease inhibitor mutations the response rates were 41% (14/34) and 43% (12/28) for REYATAZ/ritonavir and lopinavir/ritonavir, respectively. In patients with 5 or more baseline primary protease inhibitor mutations the response rates were 0% (0/9) and 23% (5/18) for REYATAZ/ritonavir and lopinavir/ritonavir, respectively.
WARNINGS
PR Interval Prolongation
The following statement was added - There have been rare reports of second-degree
AV block and other conduction abnormalities and no reports of third-degree AV
block.
Information regarding reports of first-degree AV block from Study 045 was added.
PRECAUTIONS
A subsection regarding rash was included to state that the incidence of rash
in controlled clinical trials (n=1597) was 21% . The median time to onset of
rash was 8 weeks after initiation of REYATAZ and the median duration of rash
was 1.3 weeks. Rashes were generally mild-to-moderate maculopapular skin eruptions.
Dosing with REYATAZ was often continued without interruption in patients who
developed rash. The discontinuation rate for rash in clinical studies was 0.4%.
REYATAZ should be discontinued if severe rash develops. Cases of Stevens-Johnson
syndrome and erythema multiforme have been reported in patients receiving REYATAZ.
Drug Interactions
A change to the clinical comment for the interaction between efavirenz and REYATAZ was made to distinguish the dose adjustment of REYATAZ/ritonavir/efavirenz 300/100/600 mg once daily applies to treatment-naïve subjects. Appropriate dosing recommendations for efavirenz and REYATAZ in treatment-experienced subjects have not been established.
On July 1, 2004, the VIREAD (tenofovir disoproxil fumerate) label was updated to include the following information.
The Box Warning was updated to include the following:
VIREAD IS NOT INDICATED FOR THE TREATMENT OF CHRONIC HEPATITIS B VIRUS (HBV) INFECTION AND THE SAFETY AND EFFICACY OF VIREAD HAVE NOT BEEN ESTABLISHED IN PATIENTS CO-INFECTED WITH HBV AND HIV. SEVERE ACUTE EXACERBATIONS OF HEPATITIS B HAVE BEEN REPORTED IN PATIENTS WHO ARE CO-INFECTED WITH HBV AND HIV AND HAVE DISCONTINUED VIREAD. HEPATIC FUNCTION SHOULD BE MONITORED CLOSELY WITH BOTH CLINICAL AND LABORATORY FOLLOW-UP FOR AT LEAST SEVERAL MONTHS IN PATIENTS WHO DISCONTINUE VIREAD AND ARE CO-INFECTED WITH HIV AND HBV. IF APPROPRIATE, INITIATION OF ANTI-HEPATITIS B THERAPY MAY BE WARRANTED (SEE WARNINGS).
The Warning section was also updated to include the following:
Patients Co-infected with HIV and Hepatitis B Virus
It is recommended that all patients with HIV be tested for the presence of chronic hepatitis B virus (HBV) before initiating antiretroviral therapy. VIREAD is not indicated for the treatment of chronic HBV infection and the safety and efficacy of VIREAD have not been established in patients co-infected with HBV and HIV. Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with HBV and HIV and have discontinued VIREAD. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue VIREAD and are co-infected with HIV and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
Additionally, the Clinical Pharmacology and Precaution sections were updated to include information regarding drug-drug interactions with atazanavir, adefovir and ribavirin.
No drug-drug interaction was seen between tenofovir and adefovir or tenofovir
and ribavirin.
The following text was added to the Precaution section.
Higher tenofovir concentrations could potentiate VIREAD-associated adverse events,
including renal disorders.
Atazanavir and lopinavir/ritonavir have been shown to increase tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving atazanavir and lopinavir/ritonavir and VIREAD should be monitored for VIREAD- associated adverse events. VIREAD should be discontinued in patients who develop VIREAD-associated adverse events.
VIREAD decreases the Area Under the Curve (AUC) and Minimum Concentration (Cmin)
of atazanavir. When coadministered with VIREAD, it is recommended that atazanavir
300 mg is given with ritonavir 100 mg. Atazanavir without ritonavir should not
be coadministered with VIREAD.
The Carcinogenesis, Mutagenesis, Impairment of Fertility section was revised
to include results of the long-term carcinogenicity studies in mice and rats.
The following information was included in this section.
Long-term oral carcinogenicity studies of tenofovir disoproxil fumarate in mice and rats were carried out at exposures up to approximately 16 times (mice) and 5 times (rats) those observed in humans at the therapeutic dose for HIV infection. At the high dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose.