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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
SELZENTRY (NDA-022128)
(MARAVIROC)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
10/30/2020 (SUPPL-19)
6 Adverse Reactions
6.1 Clinical Trials Experience
(Additions and/or revisions underlined)
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. The median duration of therapy with SELZENTRY was 131 weeks with 72% of subjects receiving study treatment for greater than 48 weeks and 62% of subjects receiving study treatment for 96 weeks.
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 [see Clinical Pharmacology (12.3)]. Cohort 1 received 2 single doses of SELZENTRY: the first within 3 days of birth and the second at 7 to 14 days of age. Cohort 2 received SELZENTRY twice daily for 6 weeks beginning within 3 days of birth and continued through Week 6. 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).
8 Use in Specific Populations
8.4 Pediatric Use
(Additions and/or revisions underlined)
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 [see Indications and Usage (1)], Dosage and Administration (2.4)].
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 [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)].
HIV-1–Infected Pediatric Patients Aged Older Than 6 Weeks to Less Than 2 Years: No clinical trials have been conducted in children aged older than 6 weeks to less than 2 years. Dosing recommendations for SELZENTRY in this population when concomitantly receiving noninteracting medications are based on population pharmacokinetic modeling and simulation only [see Dosage and Recommendations (2.4), Clinical Pharmacology (12.3)].
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 [see Adverse Reactions (6.1)]. 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 [see Clinical Pharmacology (12.3)].
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 [see Dosage and Administration (2.4, 2.5)].
SELZENTRY is not recommended in pre-term neonates or in pediatric patients weighing less than 2 kg.
07/18/2018 (SUPPL-18)
7 Drug Interactions
7.1 Effect of Concomitant Drugs on the Pharmacokinetics of Maraviroc(additions underlined)
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.
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE(addition underlined)
…
How should I store SELZENTRY?
Store SELZENTRY tablets and oral solution at room temperature between 68°F to 77°F (20°C to 25°C).
Throw away any unused oral solution 60 days after first opening the bottle.
Keep SELZENTRY and all medicines out of the reach of children.
…
11/04/2016 (SUPPL-17)
4 Contraindications
SELZENTRY is contraindicated in patients with severe renal impairment or ESRD (CrCl less than 30 mL per minute) who are concomitantly taking potent CYP3A inhibitors or inducers. (addition underlined)
5 Warnings and Precautions
5.1 Hepatotoxicity…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. (addition underlined)
In the Phase 2b/3 trial in treatment-naive adult subjects, 3 subjects (0.8%) who received SELZENTRY …
…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%)…
…of cardiovascular adverse events triggered by postural hypotension. Additional monitoring may be warranted.
Postural Hypotension in Patients with Renal Impairment
If adult patients with severe renal impairment or ESRD experience any symptoms … (additions underlined)
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.
In the Phase 2b/3 trial in treatment-naive adult subjects, the incidence of AIDS-defining Category C … (additions underlined)
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 …(additions underlined)
6 Adverse Reactions
6.1 Clinical Trials ExperienceAdverse Reactions in Adult Subjects (new subheading added)
…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).
… Treatment-emergent adverse events, regardless of causality, from Trials A4001027 and A4001028 are summarized in Table 5.
Table 3 renamed to Table 5 with revised title: Selected Treatment-Emergent Adverse Events (All Causality) greater than or equal to2% on SELZENTRY (and at a Higher Rate Compared with Placebo) in Trials A4001027 and A4001028 (Pooled Analysis, 48 Weeks)
Table 4 renamed to Table 6 with revised title: Maximum Shift in Laboratory Test Values (without Regard to Baseline) greater than or equal to 2% of Grade 3-4 Abnormalities (ACTG Criteria) in Trials A4001027 and A4001028 (Pooled Analysis, 48 Weeks)
Table 5 renamed to Table 7 with revised title: Selected Treatment-Emergent Adverse Events (All Causality) greater than or equal to 2% on SELZENTRY (and at a Higher Rate Compared with Efavirenz) in Trial A4001026 (96 Weeks)
Tablet 6 renamed to Table 8 with revised title: Maximum Shift in Laboratory Test Values (without Regard to Baseline) greater than or equal to 2% of Grade 3-4 Abnormalities (ACTG Criteria) in Trial A4001026 (96 Weeks)
Clinical Trials Experience in Pediatric Subjects (added section)
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. The median duration of therapy with SELZENTRY was 131 weeks with 72% of subjects receiving study treatment for greater than 48 weeks and 62% of subjects receiving study treatment for 96 weeks.
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. The most common adverse reactions (all grades) reported with twice-daily therapy with SELZENTRY, were vomiting (12%), abdominal pain (4%), diarrhea (4%), nausea (4%), and dizziness (3%). 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.
The following adverse events have been identified during post-approval 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. (additions underlined)
7 Drug Interactions
7.1 Effect of Concomitant Drugs on the Pharmacokinetics of Maraviroc… Therefore, a dosage adjustment may be required when maraviroc is coadministered with those drugs.
… levels of maraviroc and lead to loss of virologic response and possible resistance to maraviroc.
Additional drug interaction information is available.
8 Use in Specific Populations
8.1 Pregnancy(PLLR conversion)
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to SELZENTRY a 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.
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.
(PLLR conversion)
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. 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 breastfeed if 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.
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. 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 Dosage and Administration (2.4, 2.5) for dosing recommendations for pediatric patients
aged 2 years and older and weighing at least 10 kg.
…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. (additions underlined)
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. SELZENTRY is contraindicated in pediatric patients with severe renal impairment or ESRD on regular hemodialysis who are receiving potent CYP3A inhibitors.
The pharmacokinetics of maraviroc in adult subjects with mild and moderate renal impairment was similar to that in subjects with normal renal function. 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…
If adult patients with severe renal impairment or ESRD not receiving … (additions underlined)
…Maraviroc has not been studied in subjects with severe hepatic impairment or in pediatric patients with any degree of hepatic impairment. (addition underlined)
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Medication Guide(Extensive changes; please refer to label)
Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
Hepatotoxicity
Inform patients that hepatotoxicity, including life-threatening cases, has been reported with SELZENTRY; therefore, it is important to inform the healthcare professional if patients have underlying hepatitis B or C or elevations in liver-associated tests prior to treatment. Inform patients to stop SELZENTRY and seek medical evaluation immediately if they develop signs or symptoms of hepatitis or allergic reaction following use of SELZENTRY. (additions underlined)
Cardiovascular Events
When administering SELZENTRY in patients with cardiovascular comorbidities, a history of postural hypotension or receiving concomitant medication known to lower blood pressure, advise patients that they may be at increased risk for cardiovascular events. Advise patients to avoid driving or operating machinery if they experience dizziness while taking SELZENTRY.
Drug Interactions (additional section)
Advise patients to inform their healthcare provider of concomitant HIV medications as dosage of SELZENTRY may be modified depending on other HIV medications taken with SELZENTRY. Advise patients that coadministration of SELZENTRY with St. John’s wort is not recommended as it can lead to loss of virologic response and possible resistance to SELZENTRY.
Missed Dosage (additional section)
Inform patients that it is important to take SELZENTRY in combination with other antiretroviral medications on a regular dosing schedule with or without food. Advise patients to avoid missing doses as it can result in development of resistance. Instruct patients that if they miss a dose, to take it as soon as they remember. Advise patients not to double their next dose or take more than the prescribed dose.
Pregnancy
Inform patients that there is insufficient data on the safety of SELZENTRY in pregnancy. Inform patients that there is an antiretroviral pregnancy registry that monitors pregnancy outcomes in women exposed to SELZENTRY during pregnancy.
Lactation
Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk.