Selzentry Drug Information

• SELZENTRY is indicated in combination with other antiretroviral agents for the treatment of only CCR5‑tropic human immunodeficiency virus type 1 (HIV‑1) infection in adult and pediatric patients weighing at least 2 kg. Limitations of Use
• SELZENTRY is not recommended in patients with dual/mixed- or CXCR4-tropic HIV-1. SELZENTRY is a CCR5 co-receptor antagonist indicated in combination with other antiretroviral agents for the treatment of only CCR5-tropic HIV-1 infection in adults and pediatric patients weighing at least 2 kg. Limitations of Use:
• Not recommended in patients with dual/mixed- or CXCR4-tropic HIV-1.

Testing prior to Initiation of SELZENTRY Prior to initiation of SELZENTRY for treatment of HIV-1 infection, test all patients for CCR5 tropism using a highly sensitive tropism assay. SELZENTRY is recommended for patients with only CCR5-tropic HIV-1 infection. 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.

Monitor patients for alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin prior to initiation of SELZENTRY and at other time points during treatment as clinically indicated.

General Dosing Recommendations •

SELZENTRY tablets and oral solution are taken twice daily by mouth and may be taken with or without food. • SELZENTRY must be given in combination with other antiretroviral medications. • The recommended dosage of SELZENTRY differs based on concomitant medications due to drug interactions.

Recommended Dosage in Adult Patients with Normal Renal Function Table 1 displays oral dosage of SELZENTRY based on different concomitant medications. Table 1. Recommended Dosage in Adults

Recommended Dosage in Pediatric Patients with Normal Renal Function The recommended dosage of SELZENTRY should be based on body weight (kg) and should not exceed the recommended adult dose. The recommended dosage also differs based on concomitant medications due to drug interactions ( Table 2 and Table 3 ). Before prescribing SELZENTRY tablets, assess children for the ability to swallow tablets.

If a child is unable to reliably swallow SELZENTRY tablets, the oral solution formulation should be prescribed. The recommended oral dosage of SELZENTRY tablets in pediatric patients aged 2 years and older weighing at least 10 kg is presented in Table 2. Table 2.

Table 3. Recommended Dosage in Pediatric Patients Weighing at Least 2 kg (Oral Solution) Administer the oral solution using the included press-in bottle adapter and the appropriate oral dosing syringe: for doses of 2.5 mL or less, use the 3-mL syringe; for doses greater than 2.5 mL, use the 10-mL syringe. Care should be taken when measuring neonate doses due to the small volumes of oral solution required.

Recommended Dosage in Patients with Renal Impairment Adult Patients Table 4 provides dosing recommendations for patients based on renal function and concomitant medications. Table 4. Recommended Dosage in Adults Based on Renal Function CrCl = Creatinine clearance. a Potent CYP3A inhibitors (with or without a CYP3A inducer) including: clarithromycin, cobicistat, elvitegravir/ritonavir, itraconazole, ketoconazole, nefazodone, protease inhibitors (except tipranavir/ritonavir), telithromycin. b Noninteracting concomitant medications include all medications that are not potent CYP3A inhibitors or inducers such as: dolutegravir, enfuvirtide, nevirapine, all NRTIs, raltegravir, and tipranavir/ritonavir. c Dosage of SELZENTRY should be reduced to 150 mg twice daily if there are any symptoms of postural hypotension. d Potent and moderate CYP3A inducers (without a potent CYP3A inhibitor) including: carbamazepine, efavirenz, etravirine, phenobarbital, phenytoin, and rifampin.

Pediatric Patients There are no data to recommend specific doses of SELZENTRY in pediatric patients with mild or moderate renal impairment. Additionally, SELZENTRY is contraindicated for pediatric patients with severe renal impairment or end-stage renal disease (ESRD) on regular hemodialysis who are receiving potent CYP3A inhibitors or inducers.

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. Clinical Trials Experience in Adult Subjects Treatment ‑ Experienced Subjects: 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 each administered with optimized background therapy (OBT). 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 numbers of subjects reporting infections were 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.

Treatment-emergent adverse events, regardless of causality, from Trials A4001027 and A4001028 are summarized in Table 5. 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 5.

Selected Treatment-Emergent Adverse Events (All Causality) ≥2% on SELZENTRY and at a Higher Rate Compared with Laboratory Abnormalities: Table 6 shows the treatment-emergent Grade 3-4 laboratory abnormalities that occurred in greater than 2% of subjects receiving SELZENTRY. Table 6. Maximum Shift in Laboratory Test Values (without Regard to Baseline) ≥2% of Grade 3-4 Abnormalities (ACTG Criteria) in Trials A400 Treatment ‑ Naive Subjects: 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 7.

Table 7. Maximum Shift in Laboratory Test Values (without Regard to Baseline) ≥2% of Grade 3-4 Abnormalities (ACTG Criteria) in Trial A400 Less Common Adverse Events in Clinical Trials: 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 creatine kinase 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. Clinical Trials Experience in Pediatric Subjects HIV-1–Infected Pediatric Subjects: Trial A4001031 is an open-label trial in which 103 treatment-experienced, CCR5-tropic, HIV-1–infected pediatric subjects aged 2 to less than 18 years weighing at least 10 kg received SELZENTRY twice daily in combination with OBT.

The dose of SELZENTRY was based on body surface area (BSA) and on whether the subject was receiving potent CYP3A inhibitors and/or inducers. In these 103 children and adolescents, the safety profile through 96 weeks was similar to that for adults. Most of the adverse reactions reported were mild to moderate; severe (Grade 3 and 4) adverse reactions occurred in 2% of subjects.

Three subjects (3%) discontinued due to adverse events. Maraviroc-related gastrointestinal adverse events through 48 weeks (nausea, vomiting, diarrhea, constipation, and abdominal pain/cramps) were observed more commonly in subjects who received the SELZENTRY oral solution (21%) compared with those who received SELZENTRY tablets (16%). Subjects were permitted to change formulations after Week 48.

HIV-1–Exposed Neonates: The IMPAACT P2007 trial was an open-label trial in which 47 full-term HIV-1–exposed neonates (born to HIV-1–infected mothers) received at least one dose of SELZENTRY in combination with other antiretrovirals, mostly zidovudine and/or nevirapine. Both cohorts received SELZENTRY with or without exposure to maternal efavirenz (in utero only in Cohort 1, and both in utero and after birth while breastfeeding in Cohort 2). The population was 51% male and 81% black.

All infants were followed for safety through 16 weeks, with a total of 37 infants evaluable for safety. There were no additional adverse reactions observed in neonates compared with those seen in adults. All adverse reactions reported were mild to moderate.

The most common adverse reaction (all grades) reported with SELZENTRY was hemoglobin decreased (14%). One subject (3%) discontinued due to an adverse event (Grade 3 staphylococcal sepsis).

Postmarketing Experience

The following adverse events have been identified during postapproval use of SELZENTRY. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Subcutaneous Tissue Disorders Stevens‑Johnson syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), toxic epidermal necrolysis (TEN).

Effect of Concomitant Drugs on the Pharmacokinetics of Maraviroc Maraviroc is metabolized by CYP3A and is also a substrate for P-glycoprotein (P-gp), organic anion-transporting polypeptide (OATP)1B1, and multidrug resistance-associated protein (MRP)2. The pharmacokinetics of maraviroc are likely to be modulated by inhibitors and inducers of CYP3A and P-gp and may be modulated by inhibitors of OATP1B1 and MRP2. Therefore, a dosage adjustment may be required when maraviroc is coadministered with those drugs.

Concomitant use of maraviroc and St. John's wort ( Hypericum perforatum ) or products containing St. John's wort is not recommended.

Coadministration of maraviroc with St. John's wort is expected to substantially decrease maraviroc concentrations and may result in suboptimal levels of maraviroc and lead to loss of virologic response and possible resistance to maraviroc. Additional drug interaction information is available.

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 (see Data).

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 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 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.

Pediatric Use The safety and efficacy of SELZENTRY have been established in pediatric patients aged from birth to less than 18 years. The use of SELZENTRY in pediatric patients was supported by pharmacokinetic and safety data described below and by previous demonstration of efficacy in adult patients. HIV-1–Infected Pediatric Patients Aged 2 to Less Than 18 Years: The safety, pharmacokinetic 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.

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. Dosing recommendations for SELZENTRY in this population when concomitantly receiving noninteracting medications are based on population pharmacokinetic modeling and simulation only. HIV-1–Infected Neonates Aged from Birth to 6 Weeks: The recommendation of SELZENTRY for the treatment of HIV-1 infection in this pediatric population is based on safety and pharmacokinetic data obtained from clinical trial IMPAACT P2007.

In IMPAACT P2007, the safety and pharmacokinetic profiles of SELZENTRY were evaluated in full-term HIV-1–exposed neonates (born to HIV-1–infected mothers) aged from birth through 6 weeks. Pharmacokinetics were evaluated in 38 of 47 enrolled neonates who received SELZENTRY as a single dose (n = 13) or multiple doses (n = 25) up to 6 weeks of age concomitantly with other antiretrovirals (mostly zidovudine and/or nevirapine) with or without maternal exposure to efavirenz. HIV-1 status was assessed by nucleic acid test at birth, Week 6, and Week 16; all 47 enrolled neonates were HIV-1 negative at completion of the study.

There are insufficient data to make dosing recommendations for use of SELZENTRY in pediatric patients concomitantly receiving potent CYP3A inhibitors and weighing less than 10 kg, or in any pediatric patients concomitantly receiving potent CYP3A inducers without a potent CYP3A inhibitor. SELZENTRY is not recommended in pre-term neonates or in pediatric patients weighing less than 2 kg.

SELZENTRY is contraindicated in patients with severe renal impairment or ESRD (creatinine clearance less than 30 mL per minute) who are concomitantly taking potent CYP3A inhibitors or inducers.

The highest single dose administered in clinical trials was 1,200 mg. The dose-limiting adverse event was postural hypotension, which was observed at 600 mg. While the recommended dose for SELZENTRY in patients receiving a CYP3A inducer without a CYP3A inhibitor is 600 mg twice daily, this dose is appropriate due to enhanced metabolism.

Prolongation of the QT interval was seen in dogs and monkeys at plasma concentrations 6 and 12 times, respectively, those expected in humans at the intended exposure of 300-mg equivalents twice daily. However, no significant QT prolongation was seen in the trials in treatment-experienced subjects with HIV using the recommended doses of maraviroc, or in a specific pharmacokinetic trial to evaluate the potential of maraviroc to prolong the QT interval. There is no specific antidote for overdose with maraviroc.

Treatment of overdose should consist of general supportive measures including keeping the patient in a supine position, careful assessment of patient vital signs, blood pressure, and electrocardiogram. Administration of activated charcoal may also be used to aid in removal of unabsorbed drug. Hemodialysis had a minimal effect on maraviroc clearance and exposure in a trial in subjects with ESRD.