Expanded Indication for Selzentry (maraviroc)

On November 20, 2009, the Food and Drug Administration approved a supplemental NDA to expand the indication for Selzentry (maraviroc) to include combination antiretroviral treatment of therapy naive adults infected with CCR5-tropic HIV-1 virus. Maraviroc was previously approved (8/6/2007) for treatment of therapy experienced adult patients infected with CCR5-tropic HIV-1 virus. The expanded indication is based upon data collected through 96 weeks from Study A4001026, demonstrating safety and efficacy.

The new label can be found on the FDA website at Drugs@FDA.

A number of changes were made to the labeling, including:
Under HIGHLIGHTS OF PRESCRIBING INFORMATION:
RECENT MAJOR CHANGES
Indication and Usage (1)
Warnings and Precautions (5.1), (5.2), (5.4), (5.5)

Indications and Useage

SELZENTRY is a CCR5 co-receptor antagonist indicated for combination antiretroviral treatment of adults infected with only CCR5-tropic HIV-1.

• In treatment-naive subjects, more subjects treated with SELZENTRY experienced virologic failure and developed lamivudine resistance compared to efavirenz [see Microbiology (12.4) Clinical Studies (14.3].
• Tropism testing with a highly sensitive assay is required for the appropriate use of SELZENTRY (1).

Dosage and Administration

Warnings and Precautions

• More cardiovascular events including myocardial ischemia and/or infarction were observed in treatment-experienced subjects who received SELZENTRY. Use with caution in patients at increased risk of cardiovascular events (5.2).

Adverse Reactions

The most common adverse events in treatment-experienced subjects (>8% incidence) which occurred at a higher frequency compared to placebo are upper respiratory tract infections, cough, pyrexia, rash, and dizziness (6).

Under FULL PRESCRIBING INFORMATION: CONTENTS*:
6 ADVERSE REACTIONS
6.1 Clinical Trials
6.2 Postmarketing Experience
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
12.4 Microbiology
14 CLINICAL STUDIES
14.1 Studies in CCR5-tropic, Treatment-experienced Subjects
14.2 Study in Dual/Mixed-tropic, Treatment-experienced Subjects
14.3 Study in CCR5-tropic, Treatment-naive Subjects

The following changes were made to the FULL PRESCRIBING INFORMATION:

1 INDICATION AND USAGE

SELZENTRY, in combination with other antiretroviral agents, is indicated for adult patients infected with only CCR5-tropic HIV-1.

This indication is based on analyses of plasma HIV-1 RNA levels in two controlled studies of SELZENTRY in treatment-experienced subjects and one study in treatment-naive subjects. Both studies in treatment-experienced subjects were conducted in clinically advanced, 3-class antiretroviral-experienced (NRTI, NNRTI, PI, or enfuvirtide) adults with evidence of HIV-1 replication despite ongoing antiretroviral therapy.

The following points should be considered when initiating therapy with SELZENTRY:

• Adult patients infected with only CCR5-tropic HIV-1 should use SELZENTRY.
• Tropism testing must be conducted with a highly sensitive and specific tropism assay that has demonstrated the ability to identify patients appropriate for SELZENTRY use. Outgrowth of pre-existing low-level CXCR4- or dual/mixed-tropic HIV-1 not detected by tropism testing at screening has been associated with virologic failure on SELZENTRY [see Microbiology (12.4) Clinical Studies (14.3)].
  
  Use of SELZENTRY is not recommended in subjects with dual/mixed or CXCR4-tropic HIV-1 as efficacy was not demonstrated in a phase 2 study of this patient group.
• The safety and efficacy of SELZENTRY have not been established in pediatric patients.
• In treatment-naive subjects, more subjects treated with SELZENTRY experienced virologic failure and developed lamivudine resistance compared to efavirenz [see Microbiology (12.4) Clinical Studies (14.3)].

2 DOSAGE AND ADMINISTRATION

Table 1 Recommended Dosing Regimen

5 WARNINGS and precautions

5.1 Hepatotoxicity

A case of possible SELZENTRY-induced hepatotoxicity with allergic features has been reported in a study of healthy volunteers. Discontinuation of SELZENTRY should be considered in any patient with signs or symptoms of hepatitis, or with increased liver transaminases combined with rash or other systemic symptoms.

The safety and efficacy of SELZENTRY have not been specifically studied in patients with significant underlying liver disorders. In studies of treatment-experienced HIV-infected subjects, approximately 6% of subjects were co-infected with hepatitis B and approximately 6% were coinfected with hepatitis C. Due to the small number of co-infected subjects studied, no conclusions can be drawn regarding whether they are at an increased risk for hepatic adverse events with SELZENTRY administration. However, caution should be used when administering SELZENTRY to patients with pre-existing liver dysfunction or who are co-infected with viral hepatitis B or C.

5.2 Cardiovascular Events

Use with caution in patients at increased risk for cardiovascular events. Eleven subjects (1.3%) who received SELZENTRY had cardiovascular events including myocardial ischemia and/or infarction during the Phase 3 studies in treatment-experienced studies [total exposure 609 patient-years (300 on once daily + 309 on twice daily SELZENTRY)], while no subjects who received placebo had such events (total exposure 111 patient-years). These subjects generally had cardiac disease or cardiac risk factors prior to SELZENTRY use, and the relative contribution of SELZENTRY to these events is not known.

In the Phase 2b/3 study in treatment-naive subjects, 3 subjects (0.8%) who received SELZENTRY had events related to ischemic heart diseases and 5 subjects (1.4%) who received efavirenz had such events (total exposure 506 and 508 patient-years for SELZENTRY and efavirenz, respectively).

5.4 Potential Risk of Infection

SELZENTRY antagonizes the CCR5 co-receptor located on some immune cells, and therefore could potentially increase the risk of developing infections. The overall incidence and severity of infection, as well as AIDS-defining category C infections, was comparable in the treatment groups during the Phase 3 treatment-experienced studies of SELZENTRY. While there was a higher rate of certain upper respiratory tract infections reported in the SELZENTRY arm compared to placebo (23% versus 13%), there was a lower rate of pneumonia (2% vs 5%) reported in subjects receiving SELZENTRY. A higher incidence of Herpes virus infections (11 per 100 patient-years) was also reported in the SELZENTRY arm when adjusted for exposure compared to placebo (8 per 100 patient-years).

In the Phase 2b/3 study in treatment-naive subjects, the incidence of AIDS-defining Category C events when adjusted for exposure was 1.8 for SELZENTRY compared to 2.4 for efavirenz per 100 patient-years of exposure.

Patients should be monitored closely for evidence of infections while receiving SELZENTRY.

5.5 Potential Risk of Malignancy

While no increase in malignancy has been observed with SELZENTRY, due to this drug's mechanism of action it could affect immune surveillance and lead to an increased risk of malignancy.

The exposure-adjusted rate for malignancies per 100 patient-years of exposure in treatment experienced studies was 4.6 for SELZENTRY compared to 9.3 on placebo. In treatment-naive subjects, the rates were 1.0 and 2.4 per 100 patient-years of exposure for SELZENTRY and efavirenz, respectively.

Long-term follow-up is needed to more fully assess this risk.

6.1 Clinical Trials Experience

Study in Treatment-naive Subjects

Treatment-Emergent Adverse Events

Treatment-emergent adverse events, regardless of causality, from Study A4001026, a doubleblind comparative controlled study in which 721 treatment-naive subjects received SELZENTRY 300 mg BID (N=360) or efavirenz (N=361) in combination with zidovudine/lamivudine for 96 weeks, are summarized in Table 4. Selected events occurring at = 2% of subjects and at a numerically higher rate in subjects treated with SELZENTRY are included; events that occurred at the same or higher rate on efavirenz are not displayed.

Table 4
Percentage of Subjects with Selected Treatment-Emergent Adverse Events (All Causality)
(>2% on SELZENTRY and at a higher rate compared to efavirenz)

Laboratory Abnormalities

Table 5
Maximum Shift in Laboratory Test Values (Without Regard to Baseline)
Incidence =2% of Grade 3-4 Abnormalities (ACTG Criteria)
Study A4001026 (96 Weeks)

*N = total number of subjects evaluable for laboratory abnormalities.
Percentages based on total subjects evaluated for each laboratory parameter. If the same subject in a given treatment group had >1 occurrence of the same abnormality, only the most severe is counted.

Less Common Adverse Events in Clinical Trials

The following adverse events occurred in <2% of SELZENTRY-treated subjects. These events have been included because of their seriousness and either increased frequency on SELZENTRY or are potential risks due to the mechanism of action. Events attributed to the patient's underlying HIV infection are not listed.

Blood and Lymphatic System: marrow depression and hypoplastic anemia

Cardiac Disorders: unstable angina, acute cardiac failure, coronary artery disease, coronary artery occlusion, myocardial infarction, myocardial ischemia

Hepatobiliary Disorders: hepatic cirrhosis, hepatic failure, cholestatic jaundice, portal vein thrombosis, hypertransaminasemia, jaundice

Infections and Infestations: endocarditis, infective myositis, viral meningitis, pneumonia, treponema infections, septic shock, Clostridium difficile colitis, meningitis

Musculoskeletal and Connective Tissue Disorders: myositis, osteonecrosis, rhabdomyolysis, blood CK increased

Neoplasms benign, Malignant and Unspecified (including Cysts and Polyps): abdominal neoplasm, anal cancer, basal cell carcinoma, Bowen's disease, cholangiocarcinoma, diffuse large B-cell lymphoma, lymphoma, metastases to liver, esophageal carcinoma, nasopharyngeal carcinoma, squamous cell carcinoma, squamous cell carcinoma of skin, tongue neoplasm (malignant stage unspecified), anaplastic large cell lymphomas T- and null-cell types, bile duct neoplasms malignant, endocrine neoplasms malignant and unspecified

Nervous System Disorders: cerebrovascular accident, convulsions and epilepsy, tremor (excluding congenital), facial palsy, hemianopia, loss of consciousness, visual field defect

6.2 Postmarketing Experience

The following events have been identified during post-approval use of SELZENTRY. Because these reactions are reported voluntarily from a population of unknown size, it is not possible to estimate their frequency or establish a causal relationship to SELZENTRY exposure.

Skin and Subcutaneous Tissue Disorders

Stevens-Johnson syndrome.

8 USE IN SPECIFIC POPULATIONS

8.9 Race

Population pharmacokinetic analysis of pooled Phase 1/2a data indicated exposure was 26.5% higher in Asians (N=95) as compared to non-Asians (n=318). However, a study designed to evaluate pharmacokinetic differences between Caucasians (n=12) and Singaporeans (n=12) showed no difference between these two populations. No dose adjustment based on race is needed.

12 CLINICAL PHARMACOLOGY

12.2 Pharmacodynamics
Exposure Response Relationship in Treatment-Experienced Subjects
The relationship between maraviroc, modeled plasma trough concentration (Cmin) (1-9 samples per patient taken on up to 7 visits), and virologic response was evaluated in 973 treatment-experienced HIV-1-infected subjects with varied optimized background antiretroviral regimens in studies A4001027 and A4001028. The Cmin, baseline viral load, baseline CD4+ cell count and overall sensitivity score (OSS) were found to be important predictors of virologic success (defined as viral load < 400 copies/mL at 24 weeks). Table 6 illustrates the proportion of subjects with virologic success (%) within each Cmin quartile for 150 mg twice daily and 300 mg twice daily groups.

Table 6 Treatment-Experienced Subjects with Virologic Success by Cmin Quartile (Q1-Q4))

Exposure Response Relationship in Treatment-Naive Subjects The relationship between maraviroc, modeled plasma trough concentration (Cmin) (1-12 samples per patient taken on up to 8 visits), and virologic response was evaluated in 294 treatment-naive HIV-1-infected subjects receiving maraviroc 300 mg twice daily in combination with zidovudine/lamivudine in study A4001026. Table 7 illustrates the proportion of subjects with virologic success (%) within each Cmin quartile for the 300 mg twice daily dose.

Table 7 Treatment-naive Subjects with Virologic Success by Cmin Quartile (Q1-Q4)

Eighteen of 75 (24%) subjects in Q1 had no measurable maraviroc concentration on at least one occasion vs. 1 of 73 and 1 of 74 in quartiles 3 and 4 respectively.

12.3 Pharmacokinetics

Table 8 Mean Maraviroc Pharmacokinetic Parameters

* The estimated exposure is lower compared to other studies possibly due to sparse sampling, food effect, compliance and concomitant medications.

Hepatic Impairment

Maraviroc is primarily metabolized and eliminated by the liver. A study compared the pharmacokinetics of a single 300 mg dose of SELZENTRY in subjects with mild (Child-Pugh Class A, n=8), and moderate (Child-Pugh Class B, n=8) hepatic impairment to pharmacokinetics in healthy subjects (n=8). The mean Cmax and AUC were 11% and 25% higher, respectively, for subjects with mild hepatic impairment, and 32% and 46% higher, respectively, for subjects with moderate hepatic impairment compared to subjects with normal hepatic function. These changes do not warrant a dose adjustment. Maraviroc concentrations are higher when SELZENTRY 150 mg is administered with a potent CYP3A inhibitor compared to following administration of 300 mg without a CYP3A inhibitor, so patients with moderate hepatic impairment who receive SELZENTRY 150 mg with a potent CYP3A inhibitor should be monitored closely for maraviroc-associated adverse events. The pharmacokinetics of maraviroc have not been studied in subjects with severe hepatic impairment [see Warnings and Precautions (5.1)].

Effect of Concomitant Drugs on the Pharmacokinetics of Maraviroc

Maraviroc is a substrate of CYP3A and Pgp and hence its pharmacokinetics are likely to be modulated by inhibitors and inducers of these enzymes/transporters. The CYP3A/Pgp inhibitors ketoconazole, lopinavir/ritonavir, ritonavir, darunavir/ritonavir, saquinavir/ritonavir and atazanavir ± ritonavir all increased the Cmax and AUC of maraviroc [see Table 9]. The CYP3A inducers rifampin, etravirine and efavirenz decreased the Cmax and AUC of maraviroc [see Table 9].

Tipranavir/ritonavir (net CYP3A inhibitor/Pgp inducer) did not affect the steady state pharmacokinetics of maraviroc (see Table 9). Co-trimoxazole and tenofovir did not affect the pharmacokinetics of maraviroc.

Table 9 Effect of Coadministered Agents on the Pharmacokinetics of Maraviroc

* Compared to historical data

Effect of Maraviroc on the Pharmacokinetics of Concomitant Drugs
Maraviroc is unlikely to inhibit the metabolism of coadministered drugs metabolized by the following cytochrome P enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A) because maraviroc did not inhibit activity of those enzymes at clinically relevant concentrations in vitro. Maraviroc does not induce CYP1A2 in vitro.

In vitro results indicate that maraviroc could inhibit P-glycoprotein in the gut and may thus affect bioavailability of certain drugs.

Drug interaction studies were performed with maraviroc and other drugs likely to be coadministered or commonly used as probes for pharmacokinetic interactions [see Table 6]. Maraviroc had no effect on the pharmacokinetics of zidovudine or lamivudine. Maraviroc decreased the Cmin and AUC of raltegravir by 27% and 37%, respectively, which is not clinically significant. Maraviroc had no clinically relevant effect on the pharmacokinetics of midazolam, the oral contraceptives ethinylestradiol and levonorgestrel, no effect on the urinary 6ß-hydroxycortisol/cortisol ratio, suggesting no induction of CYP3A in vivo. Maraviroc had no effect on the debrisoquine metabolic ratio (MR) at 300 mg twice daily or less in vivo and did not cause inhibition of CYP2D6 in vitro until concentrations >100µM. However, there was 234% increase in debrisoquine MR on treatment compared to baseline at 600 mg once daily, suggesting potential inhibition of CYP2D6 at higher dose.

12.4 Microbiology

Cross-resistance in Cell Culture

Maraviroc had antiviral activity against HIV-1 clinical isolates resistant to NNRTIs, PIs and the fusion inhibitor enfuvirtide in cell culture (EC50 values ranged from 0.7 to 8.9 nM (0.36 to 4.57 ng/mL)). Maraviroc-resistant viruses that emerged in cell culture remained susceptible to the enfuvirtide and the protease inhibitor saquinavir.

Clinical Resistance
Virologic failure on maraviroc can result from genotypic and phenotypic resistance to maraviroc,through outgrowth of undetected CXCR4-using virus present before maraviroc treatment (see Tropism below), through resistance to background therapy drugs (Table 10), or due to low exposure to maraviroc [see Clinical Pharmacology (12.2)].

Antiretroviral treatment-experienced subjects (Studies A4001027 and A4001028)

Week 48 data from treatment-experienced subjects failing maraviroc-containing regimens with CCR5-tropic virus (n=58) have identified 22 viruses that had decreased susceptibility to maraviroc characterized in phenotypic drug assays by concentration response curves that did not reach 100% inhibition. Additionally, CCR5-tropic virus from 2 of these treatment failure subjects had =3-fold shifts in EC50 values for maraviroc at the time of failure.

Fifteen of these viruses were sequenced in the gp120 encoding region and multiple amino acid substitutions with unique patterns in the heterogeneous V3 loop region were detected. Changes at either amino acid position 308 or 323 (HXB2 numbering) were seen in the V3 loop in 7 of the subjects with decreased maraviroc susceptibility. Substitutions outside the V3 loop of gp120 may also contribute to reduced susceptibility to maraviroc.

Antiretroviral treatment-naive subjects (Study A4001026)

Treatment-naive subjects receiving SELZENTRY had more virologic failures and more treatment emergent resistance to the background regimen drugs compared to those receiving efavirenz (Table 10).

Table 10 Development of Resistance to MVC or EFV and Background Drugs in Antiretroviral Treatment-naive Trial A4001026 for Patients with CCR5-tropic Virus at Screening using Enhanced Sensitivity Trofile® Assay

*Includes subjects failing with CXCR4- or dual/mixed-tropism because these viruses are not intrinsically susceptible to maraviroc.

In an as-treated analysis of treatment-naive subjects at 96 weeks, 32 subjects failed a maraviroc-containing regimen with CCR5-tropic virus and had a tropism result at failure; 7 of these subjects had evidence of maraviroc phenotypic resistance defined as concentration response curves that did not reach 95% inhibition. One additional subject had a =3-fold shift in the EC50 value for maraviroc at the time of failure. A clonal analysis of the V3 loop amino acid envelope sequences was performed from 6 of the 7 subjects. Changes in V3 loop amino acid sequence differed between each of these different subjects, even for those infected with the same virus clade suggesting that that there are multiple diverse pathways to maraviroc resistance. The subjects who failed with CCR5-tropic virus and without a detectable maraviroc shift in susceptibility were not evaluated for genotypic resistance.

Of the 32 maraviroc virologic failures failing with CCR5-tropic virus, 20(63%) also had genotypic and/or phenotypic resistance to background drugs in the regimen (lamivudine, zidovudine).

Tropism
In both treatment-experienced and treatment-naive subjects, detection of CXCR4-using virus prior to initiation of therapy has been associated with a reduced virologic response to maraviroc.

Antiretroviral treatment-experienced subjects
In the majority of cases, treatment failure on maraviroc was associated with detection of CXCR4-using virus (i.e., CXCR4-or dual/mixed-tropic) which was not detected by the tropism assay prior to treatment. CXCR4-using virus was detected at failure in approximately 55% of subjects who failed treatment on maraviroc by week 48, as compared to 9% of subjects who experienced treatment failure in the placebo arm. To investigate the likely origin of the ontreatment CXCR4-using virus, a detailed clonal analysis was conducted on virus from 20 representative subjects (16 subjects from the maraviroc arms and 4 subjects from the placebo arm) in whom CXCR4-using virus was detected at treatment failure. From analysis of amino acid sequence differences and phylogenetic data, it was determined that CXCR4-using virus in these subjects emerged from a low level of pre-existing CXCR4-using virus not detected by the tropism assay (which is population-based) prior to treatment rather than from a co-receptor switch from CCR5-tropic virus to CXCR4-using virus resulting from mutation in the virus.

Detection of CXCR4-using virus prior to initiation of therapy has been associated with a reduced virological response to maraviroc. Furthermore, subjects failing maraviroc BID at week 48 with CXCR4-using virus had a lower median increase in CD4+ cell counts from baseline (+41 cells/mm³) than those subjects failing with CCR5-tropic virus (+162 cells/mm³). The median increase in CD4+ cell count in subjects failing in the placebo arm was +7 cells/mm³.

Antiretroviral treatment-naive subjects
In a 96-week study of antiretroviral treatment-naive subjects, 14% (12/85) who had CCR5-tropic virus at screening with an enhanced sensitivity tropism assay (Trofile®) and failed therapy on maraviroc had CXCR4-using virus at the time of treatment failure. A detailed clonal analysis was conducted in two previously antiretroviral treatment-naive subjects enrolled in a Phase 2a monotherapy study who had CXCR4-using virus detected after 10 days treatment with maraviroc. Consistent with the detailed clonal analysis conducted in treatment-experienced subjects, the CXCR4-using variants appear to emerge from outgrowth of a pre-existing undetected CXCR4-using virus. Screening with an enhanced sensitivity tropism assay reduced the number of maraviroc virologic failures with CXCR4- or dual/mixed-tropic virus at failure to 12 compared to 24 when screening with the original tropism assay. All but one (11/12; 92%) of the maraviroc failures failing with CXCR4 or dual/mixed-tropic virus also had genotypic and phenotypic resistance to the background drug lamivudine at failure and 33% (4 /12) developed zidovudine-associated resistance substitutions.

Subjects who had CCR5-tropic virus at baseline and failed maraviroc therapy with CXCR4-using virus had a median increase in CD4+ cell counts from baseline of +113 cells/mm³ while those subjects failing with CCR5-tropic virus had an increase of +135 cells/mm³. The median increase in CD4+ cell count in subjects failing in the efavirenz arm was + 95 cells/mm³.

14 CLINICAL STUDIES

The clinical efficacy and safety of SELZENTRY is derived from analyses of data from three ongoing studies in adult subjects infected with CCR5-tropic HIV-1: A4001027 and A4001028, in antiretroviral treatment-experienced adult subjects and A4001026 in treatment-naive subjects.

These studies are supported by a 48-week study in antiretroviral treatment-experienced adult subjects infected with dual/mixed-tropic HIV-1, A4001029

• Table 7 was renumbered Table 11
• Table 8 was renumbered Table 12

14.3 Study in Treatment-naive Subjects

Study A4001026 is an ongoing, randomized, double-blind, multicenter study in subjects infected with CCR5-tropic HIV-1 classified by the original Monogram Biosciences Trofile™ tropism assay. Subjects were required to have plasma HIV-1 RNA =2000 copies/mL and could not have: 1) previously received any antiretroviral therapy for >14 days, 2) an active or recent opportunistic infection or a suspected primary HIV-1 infection, or 3) phenotypic or genotypic resistance to zidovudine, lamivudine, or efavirenz. Subjects were randomized in a 1:1:1 ratio to maraviroc 300 mg once daily, maraviroc 300 mg twice daily, or efavirenz 600 mg once daily, each in combination with zidovudine/lamivudine. The efficacy and safety of SELZENTRY are based on the comparison of SELZENTRY twice daily versus efavirenz. In a pre-planned interim analysis at 16 weeks, the maraviroc 300mg once per day treatment arm failed to meet the prespecified criteria for demonstrating non-inferiority and was discontinued.

The demographic and baseline characteristics of the maraviroc and efavirenz treatment groups were comparable (Table 13). Subjects were stratified by screening HIV-1 RNA levels and by geographic region. The median CD4 cell counts and mean HIV-1 RNA at baseline were similar for both treatment groups.

Table 13 Demographic and Baseline Characteristics of Subjects in Study A4001026

The treatment outcomes at 96 weeks for study A4001026 are shown in Table 14. Treatment outcomes are based on reanalysis of the screening samples using a more sensitive tropism assay, Enhanced sensitivity Trofile® HIV tropism assay, which became available after the week 48 analysis, approximately 15% of the subjects identified as CCR5-tropic in the original analysis had Dual/Mixed- or CXCR4-tropic virus. Screening with enhanced sensitivity version of the Trofile® tropism assay reduced the number of maraviroc virologic failures with CXCR4- or Dual/Mixed-tropic virus at failure to 12 compared to 24 when screening with the original Trofile® HIV tropism assay.

Table 14: Study Outcome (Snapshot) at Week 96 Using Enhanced Sensitivity Assay †

*Week 48 results: Virologic responders (<400): 228/311 (73%) in SELZENTRY, 219/303 (72%) in Efavirenz Virologic responders (<50): 213/311 (69 %) in SELZENTRY, 207/303 (68%) in Efavirenz

†The total number of subjects (Ns) in Table 14 represents the subjects who had a CCR5-tropic virus in the reanalysis of screening samples using the more sensitive tropism assay. This reanalysis reclassified approximately 15% of subjects shown in Table 13 as having Dual/Mixed- or CXCR4-tropic virus. These numbers are different than those presented in table 13 because the numbers in Table 13 reflect the subjects with CCR5-tropic virus according to the original tropism assay. 1 Other reasons for discontinuation include lost to follow-up, withdrawn, protocol violation, and other.

The median increase from baseline in CD4+ cell counts at week 96 was 184 cells/mm³ for the SELZENTRY arm compared to 155 cells/mm³ for the efavirenz arm.

The following statement was added to the end of the PI:

Trofile® is a registered trademark of Monogram Biosciences, Inc.

4. The following changes were made to the Medication Guide:

What is SELZENTRY?

SELZENTRY is an anti-HIV medicine called a CCR5 antagonist. HIV (Human Immunodeficiency Virus) is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).

In a study of patients taking HIV medicines for the first time, the number of patients who achieved treatment success was similar in those taking either SELZENTRY or efavirenz with zidovudine and lamivudine (Combivir®). Nevertheless, in the same study, patients taking SELZENTRY along with zidovudine and lamivudine (Combivir®) failed treatment (had virus detected in their blood) and developed resistance to zidovudine (Retrovir®) or lamivudine (Epivir®) more often than patients taking efavirenz (Sustiva®) in combination with zidovudine and lamivudine (Combivir®).

SELZENTRY is used with other anti-HIV medicines in adults with CCR5-tropic HIV-1 infection. Use of SELZENTRY is not recommended in patients with dual/mixed or CXCR4-tropic HIV-1.

How does SELZENTRY work?

When used with other anti-HIV medicines, SELZENTRY may:

• reduce the amount of HIV in your blood. This is called "viral load".
• increase the number of white blood cells called T (CD4) cells.

Tell your doctor about all of your medical conditions, including if you:

• are breastfeeding or planning to breastfeed. It is recommended that HIV-positive women should not breastfeed their babies. This is because of the chance of passing HIV to your baby. You should not breastfeed if you are taking SELZENTRY because the risk to your baby is unknown. Talk with your doctor about the best way to feed your baby.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Certain other medicines may affect the levels of SELZENTRY in your blood. Your doctor may need to change your dose of SELZENTRY when you take it with certain medicines.

The levels of SELZENTRY in your blood may be changed and your healthcare provider may need to adjust your dose of SELZENTRY when taking any of the following medications together with SELZENTRY:

- darunavir (Prezista®)/ritonavir (Norvir®)
- delavirdine (Rescriptor®)
- lopinavir/ritonavir (Kaletra®)
- ketoconazole (Nizoral®)
- atazanavir (Reyataz®) ± ritonavir
- itraconazole (Sporanox®)
- saquinavir (Invirase®) ± ritonavir
- clarithromycin (Biaxin®)
- nelfinavir (Viracept®)
- nefazodone (Serzone®)
- indinavir (Crixivan®)
- telithromycin (Ketek®)
- fosamprenavir (Lexiva®)/ritonavir
- efavirenz (Sustiva®)
- etravirine (Intelence®)
- rifampin (Rifadin®)
- carbamezepine (Tegretol®)
- phenobarbital (Luminal®)
- phenytoin (Dilantin®)

The most common side effects of SELZENTRY include colds, cough, fever, rash, gastrointestinal side effects including gas and bloating, and dizziness. Tell your doctor about any side effect that bothers you or does not go away.

These are not all of the side effects with SELZENTRY. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store SELZENTRY?

• Store SELZENTRY tablets at room temperature from 59° F to 86° F (15° C to 30° C).