Selzentry

Oral Administration

Tablets and oral solution are taken twice daily

May take with or without food

Must be given in combination with other antiretroviral medications

The recommended dosage of maraviroc differs based on concomitant medications owing to drug interactions

Maraviroc is an antiviral medicine that prevents certain viral cells from multiplying in your body.

Maraviroc is used with other medications to treat CCR5-tropic human immunodeficiency virus (HIV) type 1. HIV causes the acquired immunodeficiency syndrome (AIDS).

Maraviroc is not a cure for HIV or AIDS.

Maraviroc may also be used for purposes not listed in this medication guide.

If you have severe or end-stage kidney disease, you may not be able to take maraviroc if you use certain medications, including some antibiotics or antifungal medications, some heart or blood pressure medicines, St. John's wort, and certain drugs to treat hepatitis or tuberculosis. Tell your doctor about all other medications you use.

Maraviroc may cause an allergic reaction that leads to severe liver symptoms. Stop taking maraviroc and call your doctor at once if you have: fever, itching or rash, vomiting, upper stomach pain, dark urine, or jaundice (yellowing of the skin or eyes).

You should not use maraviroc if you are allergic to it. If you have severe or end-stage kidney disease, you may not be able to take maraviroc if you use certain medications, including some antibiotics or antifungal medications, some heart or blood pressure medicines, St. John's wort, and certain drugs to treat hepatitis or tuberculosis. Tell your doctor about all other medications you use.

To make sure maraviroc is safe for you, tell your doctor if you have:

• kidney disease;
• liver disease, especially hepatitis B or C;
• heart disease;
• low blood pressure; or
• a history of stroke or circulation problems.

This medication is not expected to be harmful to an unborn baby, but HIV can be passed to your baby if you are not properly treated during pregnancy. Take all of your HIV medicines as directed to control your infection. Tell your doctor if you become pregnant during treatment.

If you are pregnant, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of maraviroc on the baby.

Women with HIV or AIDS should not breast-feed a baby. Even if your baby is born without HIV, the virus may be passed to the baby in your breast milk.

Avoid taking an herbal supplement containing St. John's wort at the same time you are taking maraviroc.

Maraviroc may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Taking this medicine will not prevent you from passing HIV to other people. Do not have unprotected sex or share razors or toothbrushes. Talk with your doctor about safe ways to prevent HIV transmission during sex. Sharing drug or medicine needles is never safe, even for a healthy person.

Many drugs can interact with maraviroc. Not all possible interactions are listed here. Tell your doctor about all your medications and any you start or stop using during treatment with maraviroc, especially:

• bosentan;
• imatinib;
• nefazodone;
• an antibiotic--clarithromycin, telithromycin;
• antifungal medicine--itraconazole, ketoconazole, posaconazole, voriconazole;
• heart medication--nicardipine, quinidine;
• hepatitis C medicine--boceprevir or telaprevir;
• seizure medicine--carbamazepine, fosphenytoin, oxcarbazepine, phenobarbital, phenytoin, primidone;
• tuberculosis medicine--isoniazid, rifabutin, rifampin, rifapentine; or
• other HIV/AIDS medications--atazanavir, darunavir, delavirdine, efavirenz, etravirine, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir.

This list is not complete and many other drugs can interact with maraviroc. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.

SELZENTRY (maraviroc) is a selective, slowly reversible, small molecule antagonist of the interaction between human CCR5 and HIV-1 gp120. Blocking this interaction prevents CCR5-tropic HIV-1 entry into cells.

SELZENTRY is available as film-coated tablets for oral administration containing either 150 or 300 mg of maraviroc and the following inactive ingredients: dibasic calcium phosphate (anhydrous), magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The film coat (Opadry® II Blue [85G20583]) contains FD&C blue #2 aluminum lake, soya lecithin, polyethylene glycol (macrogol 3350), polyvinyl alcohol, talc, and titanium dioxide.

Maraviroc is chemically described as 4,4-difluoro-N-{(1S)-3-[exo-3-(3-isopropyl-5-methyl-4H1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}cyclohexanecarboxamide.

The molecular formula is C29H41F2N5O and the structural formula is:

Maraviroc is a white to pale-colored powder with a molecular weight of 513.67. It is highly soluble across the physiological pH range (pH 1.0 to 7.5).

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

Hepatotoxicity [see BOXED WARNING, WARNINGS AND PRECAUTIONS]

Severe Skin and Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]

Cardiovascular events [see WARNINGS AND PRECAUTIONS]

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.

The safety profile of SELZENTRY is primarily based on 840 HIV-1-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 trials in subjects with CCR5-tropic HIV-1 (A4001027 and A4001028). The median duration of therapy with SELZENTRY for subjects in these trials 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. In these 2 trials, 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 Trials A4001027 and A4001028 are summarized in Table 3. Selected events occurring at greater than or equal to 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) Greater than or Equal to 2% on SELZENTRY (and at a higher rate compared with placebo) Trials A4001027 and A4001028 (Pooled Analysis, 48 Weeks)

Table 4 shows the treatment-emergent Grade 3-4 laboratory abnormalities that occurred in greater than 2% of subjects receiving SELZENTRY.

Table 4: Maximum Shift in Laboratory Test Values (without Regard to Baseline) Incidence Greater than or Equal to 2% of Grade 3-4 Abnormalities (ACTG Criteria) Trials A4001027 and A4001028 (Pooled Analysis, 48 Weeks)

Treatment-emergent Adverse Events: Treatment-emergent adverse events, regardless of causality, from Trial A4001026, a double-blind, comparative, controlled trial in which 721 treatment-naive subjects received SELZENTRY 300 mg twice daily (n = 360) or efavirenz 600 mg once daily (n = 361) in combination with lamivudine/zidovudine (COMBIVIR®) for 96 weeks, are summarized in Table 5. Selected events occurring in greater than or equal to 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) Greater than or Equal to 2% on SELZENTRY (and at a higher rate compared with efavirenz) Trial A4001026 (96 Weeks)

Table 6: Maximum Shift in Laboratory Test Values (without Regard to Baseline) Incidence Greater than or Equal to 2% of Grade 3-4 Abnormalities (ACTG Criteria) Trial A4001026 (96 Weeks)

Percentages based on total subjects evaluated for each laboratory parameter. If the same subject in a given treatment group had greater than 1 occurrence of the same abnormality, only the most severe is counted.

The following adverse events occurred in less than 2% of subjects treated with SELZENTRY or at a rate similar to the comparator. 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 subjects' underlying HIV-1 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, 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.

Postmarketing Experience

The following events have been identified during post-approval use of SELZENTRY and are not listed above. 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 exposure to SELZENTRY.

Stevens-Johnson syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), toxic epidermal necrolysis (TEN).

Read the entire FDA prescribing information for Selzentry (Maraviroc)

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Your healthcare provider will determine the best Selzentry dosage for you based on several factors including:

• other medications you are taking
• how well your kidneys function
• how your body tolerates Selzentry 

The recommended dosage range in adults is 150 mg twice daily to 600 mg twice daily.

The recommended dose in children is based on weight and should not exceed the recommended adult dose. 

Administration

Oral Administration

Administer orally twice daily without regard to food.1

Dosage

Dosage depends on whether maraviroc is administered concomitantly with drugs affecting hepatic metabolism or the P-glycoprotein transport system.200 1

Must be given in conjunction with other antiretrovirals.1

Pediatric Patients

Adolescents ≥16 years of age receiving concomitant therapy with a potent CYP3A inhibitor (e.g., protease inhibitors [PIs] [except ritonavir-boosted tipranavir], delavirdine, ketoconazole, itraconazole, clarithromycin, other potent CYP3A inhibitors [nefazodone, telithromycin]) with or without a potent CYP3A inducer: 150 mg twice daily.1 200

Adolescents ≥16 years of age receiving concomitant therapy with ritonavir-boosted tipranavir, nevirapine, nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), enfuvirtide, raltegravir, or other drugs that are not potent CYP3A inhibitors or inducers: 300 mg twice daily.1 200

Adolescents ≥16 years of age receiving concomitant therapy with a potent CYP3A inducer (e.g., efavirenz, etravirine, rifampin, carbamazepine, phenobarbital, phenytoin) and the regimen does not include a potent CYP3A inhibitor: 600 mg twice daily.1 200

Adults

Patients receiving concomitant therapy with a potent CYP3A inhibitor (e.g., PIs [except ritonavir-boosted tipranavir], delavirdine, ketoconazole, itraconazole, clarithromycin, other potent CYP3A inhibitors [nefazodone, telithromycin]) with or without a potent CYP3A inducer: 150 mg twice daily.1 200

Patients receiving concomitant therapy with ritonavir-boosted tipranavir, nevirapine, NRTIs, enfuvirtide, raltegravir, or other drugs that are not potent CYP3A inhibitors or inducers: 300 mg twice daily.1 200

Patients receiving concomitant therapy with a potent CYP3A inducer (e.g., efavirenz, etravirine, rifampin, carbamazepine, phenobarbital, phenytoin) and the regimen does not include a potent CYP3A inhibitor: 600 mg twice daily.1 200

300 mg twice daily, provided patient is not receiving a potent CYP3A inducer.199 Use in conjunction with other antiretrovirals (see Postexposure Prophylaxis following Occupational Exposure to HIV under Uses).199

Initiate PEP as soon as possible following occupational exposure to HIV (preferably within hours); continue for 4 weeks, if tolerated.199

Special Populations

Hepatic Impairment

Dosage recommendations not available.200 Plasma concentrations may be increased;1 200 use with caution.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild or moderate renal impairment (Clcr≥30 mL/minute): Dosage adjustments not necessary.1

Severe renal impairment (Clcr<30 mL/minute) or end-stage renal disease (ESRD) on regular hemodialysis receiving concomitant therapy with ritonavir-boosted tipranavir, nevirapine, NRTIs, enfuvirtide, and/or raltegravir and not receiving a potent CYP3A inhibitor or inducer: 300 mg twice daily.1 Decrease dosage to 150 mg twice daily if any symptoms of postural hypotension occur.1 (See Renal Impairment under Cautions.)

Severe renal impairment receiving concomitant therapy with a potent CYP3A inhibitor, such as a PI (except ritonavir-boosted tipranavir), delavirdine, ketoconazole, itraconazole, clarithromycin, or other potent CYP3A inhibitor (e.g., nefazodone, telithromycin): Do not use maraviroc.1

Severe renal impairment receiving concomitant therapy with potent CYP3A inducer, such as efavirenz, etravirine, rifampin, carbamazepine, phenobarbital, or phenytoin: Do not use maraviroc.1

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 [see Warnings and Precautions (5.2)]. 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.

When administering Selzentry to patients with pre-existing liver dysfunction or who are co-infected with hepatitis B and/or C virus, additional monitoring may be warranted. The safety and efficacy of Selzentry have not been specifically studied in patients with significant underlying liver disorders.

Severe Skin and Hypersensitivity Reactions

Severe, potentially life-threatening skin and hypersensitivity reactions have been reported in patients taking Selzentry, in most cases concomitantly with other drugs associated with these reactions. These include cases of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) [see Adverse Reactions (6.3)]. The cases were characterized by features including rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure. Discontinue Selzentry and other suspected agents immediately if signs or symptoms of severe skin or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, malaise, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, lip swelling, eosinophilia). Delay in stopping treatment with Selzentry or other suspect drugs after the onset of rash may result in a life-threatening reaction. Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated.

Cardiovascular Events

Eleven subjects (1.3%) who received Selzentry had cardiovascular events, including myocardial ischemia and/or infarction, during the Phase 3 trials in treatment-experienced subjects (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 trial in treatment-naive adult subjects, 3 subjects (0.8%) who received Selzentry had events related to ischemic heart disease 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-1-infected adult subjects in Phase 3 trials, postural hypotension was seen at a rate similar to placebo (approximately 0.5%).

Patients with cardiovascular comorbidities, risk factors for postural hypotension, or receiving concomitant medication known to lower blood pressure, could be at increased risk of cardiovascular adverse events triggered by postural hypotension. Additional monitoring may be warranted.

Postural Hypotension in Patients with Renal Impairment

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 adult 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 (2.5)].

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Selzentry. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as infection with Mycobacterium avium infection, cytomegalovirus, Pneumocystisjirovecii pneumonia [PCP], tuberculosis, or reactivation of Herpessimplex and Herpeszoster), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of 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, were comparable in the treatment groups during the Phase 3 adult treatment-experienced trials of Selzentry. While there was a higher rate of certain upper respiratory tract infections reported in the treatment arm receiving Selzentry compared with placebo (23% versus 13%), there was a lower rate of pneumonia (2% versus 5%) reported in subjects receiving Selzentry. A higher incidence of Herpes virus infections (11 per 100 patient-years) was also reported in the treatment arm receiving Selzentry when adjusted for exposure compared with placebo (8 per 100 patient-years).

In the Phase 2b/3 trial in treatment-naive adult 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 adult treatment-experienced trials was 4.6 for Selzentry compared with 9.3 on placebo. In treatment-naive adult 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.

Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Selzentry during pregnancy. Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary

Limited data on the use of Selzentry during pregnancy from the APR and case reports are not sufficient to inform a drug-associated risk of birth defects and miscarriage. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with maraviroc. During organogenesis in the rat and rabbit, systemic exposures (AUC) to maraviroc were approximately 20 times (rats) and 5 times (rabbits) the exposure in humans at the recommended 300-mg twice-daily dose. In the rat pre- and post-natal development study, maternal systemic exposure (AUC) to maraviroc was approximately 14 times the exposure in humans at the recommended 300-mg twice-daily dose [seeData].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data: Maraviroc was administered orally to pregnant rats (up to 1,000 mg per kg per day) and rabbits (up to 75 mg per kg per day) on gestation Days 6 to 17 and 7 to 19, respectively. No adverse effects on embryo-fetal development were observed at these dose levels, resulting in exposures (AUC) approximately 20 times (rats) and 5 times (rabbits) higher than human exposures at the recommended daily dose. In the rat pre- and post-natal development study, maraviroc was administered orally at up to 1,000 mg per kg per day on gestation Day 6 to lactation/post-partum Day 20, with development of the offspring (including fertility and reproductive performance) unaffected by maternal administration of maraviroc at an exposure (AUC) approximately 14 times higher than human exposure at the recommended daily dose.

Lactation

Risk Summary

The Centers for Disease Control and Prevention recommend that HIV‑1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV‑1 infection.

There are no data on the presence of maraviroc in human milk, the effects on the breastfed infant, or the effects on milk production. When administered to lactating rats, maraviroc was present in milk [see Data]. Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) serious adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeedif they are receiving Selzentry.

Data

Maraviroc (and related metabolites) was excreted into the milk of lactating rats following a single oral dose of maraviroc (100 mg per kg) on lactation Day 12, with a maximal milk concentration achieved one hour post-administration at a milk concentration approximately 2.5 times that of maternal plasma concentrations.

Pediatric Use

The safety, pharmacokinetic (PK) profile, and antiviral activity of Selzentry were evaluated in treatment-experienced, CCR5-tropic, HIV-1-infected pediatric subjects aged 2 to less than 18 years weighing at least 10 kg in an open-label, multicenter clinical trial, A4001031 [see Adverse Reactions (6.1), Clinical Studies (14.2)]. Pharmacokinetics were evaluated in a total of 98 pediatric subjects: 85 subjects received Selzentry and concomitant medications that included potent CYP3A inhibitors with or without potent CYP3A inducers, 10 subjects received Selzentry and noninteracting medications (not containing potent CYP3A inhibitors or potent CYP3A inducers), and three subjects received Selzentry and medications that included potent CYP3A inducers without potent CYP3A inhibitors [see Clinical Pharmacology (12.3)].

See Dosage and Administration (2.4, 2.5) for dosing recommendations for pediatric patients aged 2 years and older and weighing at least 10 kg. The pharmacokinetics, safety, and efficacy of maraviroc in patients younger than 2 years have not been established. Therefore, Selzentry is not recommended in this patient population. Additionally, there are insufficient data to make dosing recommendations for use of Selzentry in pediatric patients concomitantly receiving noninteracting medications and weighing less than 30 kg or in pediatric patients concomitantly receiving potent CYP3A inducers without a potent CYP3A inhibitor [see Dosage and Administration (2.4, 2.5)].

Geriatric Use

There were insufficient numbers of subjects aged 65 and over in the clinical trials to determine whether they respond differently from younger subjects. In general, caution should be exercised when administering Selzentry in elderly patients, also reflecting the greater frequency of decreased hepatic and renal function, of concomitant disease and other drug therapy.

Renal Impairment

Recommended doses of Selzentry for adult patients with impaired renal function (CrCl less than or equal to 80 mL per minute) are based on the results of a pharmacokinetic trial conducted in healthy adult subjects with various degrees of renal impairment. Maraviroc has not been studied in pediatric patients with renal impairment. There are no data to recommend specific doses of Selzentry in pediatric patients with mild to moderate renal impairment [see Use in Specific Populations (8.4)]. Selzentry is contraindicated in pediatric patients with severe renal impairment or ESRD on regular hemodialysis who are receiving potent CYP3A inhibitors [see Contraindications (4)].

The pharmacokinetics of maraviroc in adult subjects with mild and moderate renal impairment was similar to that in subjects with normal renal function [see Clinical Pharmacology (12.3)]. A limited number of adult subjects with mild and moderate renal impairment in the Phase 3 clinical trials (n = 131 and n = 12, respectively) received the same dose of Selzentry as that administered to subjects with normal renal function. In these subjects there was no apparent difference in the adverse event profile for maraviroc compared with subjects with normal renal function.

If adult patients with severe renal impairment or ESRD not receiving a concomitant potent CYP3A inhibitor or inducer experience any symptoms of postural hypotension while taking Selzentry 300 mg twice daily, the dose should be reduced to 150 mg twice daily. No trials have been performed in subjects with severe renal impairment or ESRD co-treated with potent CYP3A inhibitors or inducers. Hence, no dose of Selzentry can be recommended, and Selzentry is contraindicated for these patients [see Dosage and Administration (2.3), Contraindications (4), Warnings and Precautions (5.3), Clinical Pharmacology (12.3)].

Hepatic Impairment

Maraviroc is principally metabolized by the liver; therefore, when administering this drug to patients with hepatic impairment, maraviroc concentrations may be increased. Maraviroc concentrations are higher when Selzentry 150 mg is administered with a potent CYP3A inhibitor compared with 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. Maraviroc has not been studied in subjects with severe hepatic impairment or in pediatric patients with any degree of hepatic impairment [see Warnings and Precautions (5.1), Clinical Pharmacology (12.3)].

Gender

Population pharmacokinetic analysis of pooled Phase 1/2a data indicated gender (female: n = 96, 23.2% of the total population) does not affect maraviroc concentrations. Dosage adjustment based on gender is not necessary.

Race

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

Selzentry film-coated tablets are available as follows:

25-mg, 75-mg, 150-mg, and 300-mg tablets are blue, biconvex, oval, film-coated tablets debossed with “MVC 25”, “MVC 75”, “MVC 150”, or “MVC 300”, respectively, on one side and plain on the other.

25-mg tablets: Bottle of 120 tablets (NDC 49702-233-08).

75-mg tablets: Bottle of 120 tablets (NDC 49702-235-08).

150-mg tablets: Bottle of 60 tablets (NDC 49702-223-18).

300-mg tablets: Bottle of 60 tablets (NDC 49702-224-18).

Selzentry film-coated tablets should be stored at 20oC to 25oC (68oF to 77oF); excursions permitted between 15oC and 30oC (59oF and 86oF) [see USP Controlled Room Temperature].

Selzentry oral solution is a clear, colorless, strawberry-flavored liquid. Each mL of the solution contains 20 mg of maraviroc. It is packaged in plastic bottles as follows:

Bottle of 230 mL (NDC 49702-237-55). Each bottle is packaged with one press-in bottle adapter and one 10–mL oral dosing syringe with 0.5–mL gradations. The press-in bottle adapter and oral dosing syringe are not made with natural rubber latex. This product does not require reconstitution.

Selzentry oral solution should be stored at 20oC to 25oC (68oF to 77oF); excursions permitted between 15oC and 30oC (59oF and 86oF) [see USP Controlled Room Temperature].