Food and Drug Administration - November 24, 2009

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

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-naïve 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-naïve 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

5.2 Cardiovascular Events

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-naïve 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 treatmentexperienced
studies was 4.6 for SELZENTRY compared to 9.3 on placebo. In treatment-naïve
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-Naïve Subjects

Treatment-Emergent Adverse Events

Treatment-emergent adverse events, regardless of causality, from Study A4001026, a doubleblind
comparative controlled study in which 721 treatment-naïve 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:

Cardiac Disorders:

Hepatobiliary Disorders:

Infections and Infestations:

Musculoskeletal and Connective Tissue Disorders:

Neoplasms benign, Malignant and Unspecified (including Cysts and Polyps):

Nervous System Disorders

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

12 CLINICAL PHARMACOLOGY

12.2 Pharmacodynamics

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-Naïve 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-naïve subjects (Study A4001026)

Treatment-naïve 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-Naïve
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-naïve 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-naïve subjects
In a 96-week study of antiretroviral treatment-naïve 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-naïve
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

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

14.3 Study in Treatment-Naïve Subjects

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:

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

T

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

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).

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

091124
FD091106

SOURCE: Food and Drug Administration (FDA).

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