Selzentry

maraviroc

Dosage Form: tablet, film coated
FULL PRESCRIBING INFORMATION

 Hepatotoxicity has been reported with use of Selzentry. Severe rash or evidence of a systemic allergic reaction (e.g., fever, eosinophilia, or elevated IgE) prior to the development of hepatotoxicity may occur. Patients with signs or symptoms of hepatitis or allergic reaction following use of Selzentry should be evaluated immediately [see Warnings and Precautions (5.1)].

Indications and Usage for Selzentry

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 2 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 (nucleoside reverse transcriptase inhibitor [NRTI], non-nucleoside reverse transcriptase inhibitor [NNRTI], protease inhibitor [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 tropism assay that has demonstrated the ability to identify patients appropriate for use of Selzentry. 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 with efavirenz [see Microbiology (12.4), Clinical Studies (14.3)].

Selzentry Dosage and Administration

Dose Recommendations for Patients With Normal Renal Function

The recommended dose of Selzentry differs based on concomitant medications due to drug interactions (see Table 1). Selzentry can be taken with or without food. Selzentry must be given in combination with other antiretroviral medications.

Table 1 gives the recommended dose adjustments [see Drug Interactions (7.1)].

Table 1. Recommended Dosing Regimen

Concomitant Medications	Dose of Selzentry
Potent CYP3A inhibitors (with or without a potent CYP3A inducer) including: protease inhibitors (except tipranavir/ritonavir) delavirdine ketoconazole, itraconazole, clarithromycin other potent CYP3A inhibitors (e.g., nefazodone, telithromycin)	150 mg twice daily
Other concomitant medications, including tipranavir/ritonavir, nevirapine, raltegravir, all NRTIs, and enfuvirtide	300 mg twice daily
Potent CYP3A inducers (without a potent CYP3A inhibitor) including: efavirenz rifampin etravirine carbamazepine, phenobarbital, and phenytoin	600 mg twice daily

Dose Recommendations for Patients With Renal Impairment

Table 2 provides dosing recommendations for patients based on renal function and concomitant medications.

Table 2. Recommended Dosing Regimens Based on Renal Function

Concomitant Medicationsa	Dose of Selzentry Based on Renal Function
	Normal (CrCl>80 mL/min)	Mild (CrCl >50 and ≤80 mL/min)	Moderate (CrCl ≥30 and ≤50 mL/min)	Severe (CrCl <30 mL/min)	End-Stage Renal Disease (ESRD) On Regular Hemodialysis
Potent CYP3A inhibitors (with or without a CYP3A inducer)a	150 mg twice daily	150 mg twice daily	150 mg twice daily	NR	NR
Other concomitant medicationsa	300 mg twice daily	300 mg twice daily	300 mg twice daily	300 mg twice dailyb	300 mg twice dailyb
Potent CYP3A Inducers (without a potent CYP3A inhibitor)a	600 mg twice daily	600 mg twice daily	600 mg twice daily	NR	NR

NR = Not recommended.

a See Table 1 for the list of concomitant medications.

b The dose of Selzentry should be reduced to 150 mg twice daily if there are any symptoms of postural hypotension [see Warnings and Precautions (5.2)].

Dosage Forms and Strengths

• 150-mg blue, oval, film-coated tablets debossed with “MVC 150” on one side and plain on the other.


• 300-mg blue, oval, film-coated tablets debossed with “MVC 300” on one side and plain on the other.

Contraindications

Selzentry should not be used in patients with severe renal impairment or end-stage renal disease (ESRD) (CrCl <30 mL/min) who are taking potent CYP3A inhibitors or inducers.

Warnings and Precautions

Hepatotoxicity

  Hepatotoxicity with allergic features including life-threatening events has been reported in clinical trials and postmarketing. Severe rash or evidence of systemic allergic reaction including drug-related rash with fever, eosinophilia, elevated IgE, or other systemic symptoms have been reported in conjunction with hepatotoxicity. These events occurred approximately 1 month after starting treatment. Among reported cases of hepatitis, some were observed in the absence of allergic features or with no pre-existing hepatic disease.

  Appropriate laboratory testing including ALT, AST, and bilirubin should be conducted prior to initiating therapy with Selzentry and at other time points during treatment as clinically indicated. Hepatic laboratory parameters should be obtained in any patient who develops rash, or signs or symptoms of hepatitis, or allergic reaction. 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.

  Caution should be used when administering Selzentry to patients with pre-existing liver dysfunction or who are coinfected with viral hepatitis B or C. 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 co-infected 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 administration of Selzentry.

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 Selzentry once daily + 309 on Selzentry twice daily]), 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 use of Selzentry, 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).

When Selzentry was administered to healthy volunteers at doses higher than the recommended dose, symptomatic postural hypotension was seen at a greater frequency than in placebo. However, when Selzentry was given at the recommended dose in HIV subjects in Phase 3 studies, postural hypotension was seen at a rate similar to placebo (approximately 0.5%). Caution should be used when administering Selzentry in patients with a history of postural hypotension or on concomitant medication known to lower blood pressure.

Postural Hypotension in Patients With Renal Impairment: Patients with impaired renal function may have cardiovascular co-morbidities and could be at increased risk of cardiovascular adverse events triggered by postural hypotension. An increased risk of postural hypotension may occur in patients with severe renal insufficiency or in those with ESRD due to increased maraviroc exposure in some patients. Selzentry should be used in patients with severe renal impairment or ESRD only if they are not receiving a concomitant potent CYP3A inhibitor or inducer. However, the use of Selzentry in these patients should only be considered when no alternative treatment options are available. If patients with severe renal impairment or ESRD experience any symptoms of postural hypotension while taking 300 mg twice daily, the dose should be reduced to 150 mg twice daily [see Dosage and Administration (2.2)].

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including maraviroc. 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 infection with Mycobacterium avium, cytomegalovirus, Pneumocystis jirovecii, Mycobacterium tuberculosis, or reactivation of Herpes simplex and Herpes zoster), which may necessitate further evaluation and treatment.

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 arm receiving Selzentry compared with 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 arm receiving Selzentry when adjusted for exposure compared with 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 with 2.4 for efavirenz per 100 patient-years of exposure.

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

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 with 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.

Adverse Reactions

The following adverse reactions are discussed in other sections of the labeling:

• Hepatotoxicity [see Boxed Warning, Warnings and Precautions (5.1)]


• Cardiovascular events [see Warnings and Precautions (5.2)]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Studies in Treatment-Experienced Subjects: The safety profile of Selzentry is primarily based on 840 HIV-infected subjects who received at least 1 dose of Selzentry during two Phase 3 trials. A total of 426 of these subjects received the indicated twice-daily dosing regimen.

Assessment of treatment-emergent adverse events is based on the pooled data from 2 studies in subjects with CCR5-tropic HIV-1 (A4001027 and A4001028). The median duration of therapy with Selzentry for subjects in these studies was 48 weeks, with the total exposure on Selzentry twice daily at 309 patient-years versus 111 patient-years on placebo + optimized background therapy (OBT). The population was 89% male and 84% white, with mean age of 46 years (range: 17 to 75 years). Subjects received dose equivalents of 300 mg maraviroc once or twice daily.

The most common adverse events reported with twice-daily therapy with Selzentry with frequency rates higher than placebo, regardless of causality, were upper respiratory tract infections, cough, pyrexia, rash, and dizziness. Additional adverse events that occurred with once-daily dosing at a higher rate than both placebo and twice-daily dosing were diarrhea, edema, influenza, esophageal candidiasis, sleep disorders, rhinitis, parasomnias, and urinary abnormalities. In these 2 studies, the rate of discontinuation due to adverse events was 5% for subjects who received Selzentry twice daily + OBT as well as those who received placebo + OBT. Most of the adverse events reported were judged to be mild to moderate in severity. The data described below occurred with twice-daily dosing of Selzentry.

The total number of subjects reporting infections were 233 (55%) and 84 (40%) in the group receiving Selzentry twice daily and the placebo group, respectively. Correcting for the longer duration of exposure on Selzentry compared with placebo, the exposure-adjusted frequency (rate per 100 subject-years) of these events was 133 for both Selzentry twice daily and placebo.

Dizziness or postural dizziness occurred in 8% of subjects on either Selzentry or placebo, with 2 subjects (0.5%) on Selzentry permanently discontinuing therapy (1 due to syncope, 1 due to orthostatic hypotension) versus 1 subject on placebo (0.5%) permanently discontinuing therapy due to dizziness.

Treatment-emergent adverse events, regardless of causality, from A4001027 and A4001028 are summarized in Table 3. 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 placebo are not displayed.

Table 3. Percentage of Subjects With Selected Treatment-Emergent Adverse Events (All Causality)(≥2% on Selzentry and at a higher rate compared with placebo) Studies A4001027 and A4001028 (Pooled Analysis, 48 Weeks)

	Selzentry Twice Dailya		Placebo
	N = 426 (%)	Exposure-adjusted rate (per 100 pt-yrs) PYE = 309b	N = 426 (%)	Exposure-adjusted rate (per 100 pt-yrs) PYE = 111b
Eye Disorders
Conjunctivitis	2	3	1	3
Ocular infections, inflammations, and associated manifestations	2	3	1	2
Gastrointestinal Disorders
Constipation	6	9	3	6
General Disorders and Administration Site Conditions
Pyrexia	13	20	9	17
Pain and discomfort	4	5	3	5
Infections and Infestations
Upper respiratory tract infection	23	37	13	27
Herpes infection	8	11	4	8
Sinusitis	7	10	3	6
Bronchitis	7	9	5	9
Folliculitis	4	5	2	4
Pneumonia	2	3	5	10
Anogenital warts	2	3	1	3
Influenza	2	3	0.5	1
Otitis media	2	3	0.5	1
Metabolism and Nutrition Disorders
Appetite disorders	8	11	7	13
Musculoskeletal and Connective Tissue Disorders
Joint-related signs and symptoms	7	10	3	5
Muscle pains	3	4	0.5	1
Neoplasms Benign, Malignant, and Unspecified
Skin neoplasms benign	3	4	1	3
Nervous System Disorders
Dizziness/postural dizziness	9	13	8	17
Paresthesias and dysesthesias	5	7	3	6
Sensory abnormalities	4	6	1	3
Disturbances in consciousness	4	5	3	6
Peripheral neuropathies	4	5	3	6
Psychiatric Disorders
Disturbances in initiating and maintaining sleep	8	11	5	10
Depressive disorders	4	6	3	5
Anxiety symptoms	4	5	3	7
Renal and Urinary Disorders
Bladder and urethral symptoms	5	7	1	3
Urinary tract signs and symptoms	3	4	1	3
Respiratory, Thoracic, and Mediastinal Disorders
Coughing and associated symptoms	14	21	5	10
Upper respiratory tract signs and symptoms	6	9	3	6
Nasal congestion and inflammations	4	6	3	5
Breathing abnormalities	4	5	2	5
Paranasal sinus disorders	3	4	0.5	1
Skin and Subcutaneous Tissue Disorders
Rash	11	16	5	11
Apocrine and eccrine gland disorders	5	7	4	7.5
Pruritus	4	5	2	4
Lipodystrophies	3	5	0.5	1
Erythemas	2	3	1	2
Vascular Disorders
Vascular hypertensive disorders	3	4	2	4

a300-mg dose equivalent. 

bPYE = Patient-years of exposure.

Laboratory Abnormalities: Table 4 shows the treatment-emergent Grade 3-4 laboratory abnormalities that occurred in >2% of subjects receiving Selzentry.

Table 4. Maximum Shift in Laboratory Test Values (Without Regard to Baseline)

Incidence ≥2% of Grade 3-4 Abnormalities (ACTG Criteria) Studies A4001027 and A4001028 (Pooled Analysis, 48 Weeks)

Laboratory Parameter Preferred Term	Limit	Selzentry Twice Daily + OBT (N = 421)a %	Placebo + OBT (N = 207)a %
Aspartate aminotransferase	>5.0x ULN	4.8	2.9
Alanine aminotransferase	>5.0x ULN	2.6	3.4
Total bilirubin	>5.0x ULN	5.5	5.3
Amylase	>2.0x ULN	5.7	5.8
Lipase	>2.0x ULN	4.9	6.3
Absolute neutrophil count	<750/mm3	4.3	2.4

aPercentages based on total subjects evaluated for each laboratory parameter.

Study in Treatment-Naive Subjects:Treatment-Emergent Adverse Events: Treatment-emergent adverse events, regardless of causality, from Study A4001026, a double-blind, comparative, controlled study in which 721 treatment-naive subjects received Selzentry 300 mg twice daily (N = 360) or efavirenz (N = 361) in combination with zidovudine/lamivudine for 96 weeks, are summarized in Table 5. 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 5. Percentage of Subjects With Selected Treatment-Emergent Adverse Events (All Causality) (≥2% on Selzentry and at a higher rate compared with efavirenz) Study A4001026 (96 Weeks)

	Selzentry 300 mg Twice Daily + Zidovudine/Lamivudine (N = 360) %	Efavirenz 600 mg Once Daily + Zidovudine/Lamivudine (N = 361) %
Blood and Lymphatic System Disorders
Anemias NEC	8	5
Neutropenias	4	3
Ear and Labyrinth Disorders
Ear disorders NEC	3	2
Gastrointestinal Disorders
Flatulence, bloating, and distention	10	7
Gastrointestinal atonic and hypomotility disorders NEC	9	5
Gastrointestinal signs and symptoms NEC	3	2
General Disorders and Administration Site Conditions
Body temperature perception	3	1
Infections and Infestations
Bronchitis	13	9
Herpes infection	7	6
Upper respiratory tract infection	32	30
Bacterial infections NEC	6	3
Herpes zoster/varicella	5	4
Lower respiratory tract and lung infections	3	2
Neisseria infections	3	0
Tinea infections	4	3
Viral infections NEC	3	2
Musculoskeletal and Connective Tissue Disorders
Joint-related signs and symptoms	6	5
Nervous System Disorders
Memory loss (excluding dementia)	3	1
Paresthesias and dysesthesias	4	3
Renal and Urinary Disorders
Bladder and urethral symptoms	4	3
Reproductive System and Breast Disorders
Erection and ejaculation conditions and disorders	3	2
Respiratory, Thoracic, and Mediastinal Disorders
Upper respiratory tract signs and symptoms	9	5
Skin and Subcutaneous Disorders
Acnes	3	2
Alopecias	2	1
Lipodystrophies	4	3
Nail and nail bed conditions (excluding infections and infestations)	6	2