Tolerability Profile
| MERIT: The most common adverse events (>8% incidence) reported with SELZENTRY with frequency rates higher than efavirenz, regardless of causality | ||
| SELZENTRY 300 mg bid + zidovudine/lamivudine (N=360), % |
Efavirenz 600 mg qd + zidovudine/lamivudine (N=361), % |
|
| Upper respiratory tract infection | 32 | 30 |
| Bronchitis | 13 | 9 |
| Flatulence, bloating, and distention | 10 | 7 |
| Upper respiratory tract signs and symptoms | 9 | 5 |
| GI atonic and hypomotility disorders NEC | 9 | 5 |
bid=twice daily.
qd=once daily.
NEC=not elsewhere classified.
Discontinuations in MERIT:
- At 96 weeks:
- Fewer SELZENTRY patients than efavirenz patients discontinued due to adverse events (all causality: 6% vs 16%, respectively)
- More patients treated with SELZENTRY than patients treated with efavirenz discontinued due to lack of efficacy (13% vs 6%, respectively)1
For a complete list of treatment-emergent adverse events (all causality) ≥2% on SELZENTRY and at a higher rate compared with efavirenz, please see full Prescribing Information.
Analysis Background
Based on an analysis of study A4001026 (MERIT), a randomized, blinded, noninferiority trial comparing SELZENTRY 300 mg bid and qd vs efavirenz 600 mg qd, both administered with zidovudine/lamivudine, in treatment-naïve adult patients with only CCR5-tropic HIV-1.
The entire MERIT patient population remained in safety and tolerability analysis for the broadest possible assessment of these important parameters.
Pooled analysis of the MOTIVATE 1 and MOTIVATE 2* studies
| The most common adverse events (>8% incidence) reported with SELZENTRY with frequency rates higher than placebo, regardless of causality | ||
| SELZENTRY 300 mg bid† + OBT (N=426;PYE=309),% |
Placebo + OBT (N=209;PYE=111),% | |
| Upper respiratory tract infection | 23 | 13 |
| Cough | 14 | 5 |
| Pyrexia | 13 | 9 |
| Rash | 11 | 5 |
| Dizziness | 9 | 8 |
bid=twice daily.
OBT=optimized background therapy.
PYE=patient years of exposure.
*MOTIVATE 1 and MOTIVATE 2 are studies A4001027 and A4001026, respectively.
†300-mg dose equivalent.
For a complete list of treatment-emergent adverse events (all causality) ≥2% on SELZENTRY and at a higher rate compared with efavirenz, please see full Prescribing Information.
Discontinuations in MOTIVATE:
- The rate of discontinuation due to adverse events for patients treated with SELZENTRY twice daily + OBT was 4% vs 5% for patients treated with placebo + OBT
- Most of the adverse events reported in MOTIVATE 1 & 2 were judged to be mild to moderate in severity
IMPORTANT SAFETY INFORMATION
WARNING: Hepatotoxicity: See full Prescribing Information for complete Boxed Warning.
Hepatotoxicity has been reported, which may be preceded by severe rash or other features of a systemic allergic reaction (eg, fever, eosinophilia or elevated IgE). Immediately evaluate patients with signs or symptoms of hepatitis or allergic reaction.
INDICATION AND USAGE
SELZENTRY, in combination with other antiretroviral agents, is indicated for adult patients infected with only CCR5-tropic HIV-1.
This indication is based on analyses of plasma HIV-1 RNA levels in two controlled studies of SELZENTRY in treatment-experienced patients and one study in treatment-naïve patients. Both studies in treatment-experienced patients were conducted in clinically advanced, 3-class antiretroviral-experienced (NRTI, NNRTI, PI, or enfuvirtide) adults with evidence of HIV-1 replication despite ongoing antiretroviral therapy.
The following points should be considered when initiating therapy with SELZENTRY:
- Adult patients infected with only CCR5-tropic HIV-1 should use SELZENTRY
- Tropism testing must be conducted with a highly sensitive tropism assay that has demonstrated the ability to identify patients appropriate for SELZENTRY use. Outgrowth of pre-existing low-level CXCR4- or dual/mixed-tropic HIV-1 not detected by tropism testing at screening has been associated with virologic failure on SELZENTRY
- Use of SELZENTRY is not recommended in patients with dual/mixed or CXCR4-tropic HIV-1 as efficacy was not demonstrated in a Phase 2 study of this patient group
- The safety and efficacy of SELZENTRY have not been established in pediatric patients
- In treatment-naïve patients, more patients treated with SELZENTRY experienced virologic failure and developed lamivudine resistance compared with efavirenz
IMPORTANT SAFETY INFORMATION
WARNING: Hepatotoxicity: See full Prescribing Information for complete Boxed Warning.
Hepatotoxicity has been reported, which may be preceded by severe rash or other features of a systemic allergic reaction (eg, fever, eosinophilia or elevated IgE). Immediately evaluate patients with signs or symptoms of hepatitis or allergic reaction.
CONTRAINDICATION
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 cytochrome P450 (CYP) 3A inhibitors or inducers.
ADDITIONAL WARNINGS AND PRECAUTIONS
Hepatotoxicity
Hepatotoxicity accompanied by severe rash or systemic allergic reaction including potentially life-threatening events has been reported in clinical trials and postmarketing. These events occurred approximately one 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.
Hepatic laboratory parameters including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin should be obtained prior to starting SELZENTRY and at other time points during treatment as clinically indicated. If rash or symptoms or signs of hepatitis or allergic reaction develop, hepatic laboratory parameters should be monitored and discontinuation of treatment should be considered.
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.
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). 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. 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
Use with caution in patients at increased risk of cardiovascular events, because cardiovascular events, including myocardial ischemia and/or infarction, were observed in treatment-experienced and treatment-naïve patients who received SELZENTRY.
Caution should be used when administering SELZENTRY in patients with a history of postural hypotension or who receive concomitant medication known to lower blood pressure. Patients should be advised that if they experience dizziness while receiving SELZENTRY, they should avoid driving or operating machinery.
Postural hypotension in patients with renal impairment
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 due to an increased risk of postural hypotension as a result of increased SELZENTRY 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 and no alternative treatment options are available. If 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.
Immune reconstitution syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including SELZENTRY.
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 coreceptor located on some immune cells, and therefore, could potentially increase the risk of developing infections. Patients should be monitored closely for evidence of infection 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. Long-term follow-up is needed to more fully assess this risk.
MOST COMMON ADVERSE EVENTS
In treatment-experienced patients, the most common adverse events (>8%) reported with SELZENTRY twice-daily therapy with frequency rates higher than placebo, regardless of causality, were upper respiratory tract infections (23% vs 13%), cough (14% vs 5%), pyrexia (13% vs 9%), rash (11% vs 5%), and dizziness (9% vs 8%).
In treatment-naïve patients, the most common adverse events (>8%) reported with SELZENTRY twice-daily therapy with frequency rates higher than efavirenz, regardless of causality, were upper respiratory tract infection (32% vs 30%), bronchitis (13% vs 9%), flatulence, bloating, and distention (10% vs 7%), upper respiratory tract signs and symptoms (9% vs 5%), and GI atonic and hypomotility disorders not elsewhere classified (NEC) (9% vs 5%).
USE IN SPECIFIC PATIENT POPULATIONS
Pediatric Patients: There are no data available in pediatric patients; therefore, SELZENTRY should not be used in patients <16 years of age.
Hepatic Impairment: SELZENTRY is principally metabolized by the liver; therefore, caution should be exercised when administering this drug to patients with hepatic impairment, because SELZENTRY concentrations may be increased.
CONCOMITANT USE
SELZENTRY is a substrate of CYP3A and P-glycoprotein (P-gp). Coadministration with potent CYP3A inhibitors, including protease inhibitors (except tipranavir/ritonavir) or delavirdine, will increase the concentration of SELZENTRY. Coadministration with potent CYP3A inducers, including efavirenz, may decrease the concentration of SELZENTRY. Healthcare providers should ensure that an appropriate dose adjustment of SELZENTRY is made when SELZENTRY is coadministered with potent CYP3A inhibitors and/or potent CYP3A inducers since concentrations, therapeutic effects, and the safety of SELZENTRY may be affected.
Concomitant use of SELZENTRY and St. John's Wort (Hypericum perforatum) or products containing St. John's Wort is not recommended.
HOW SUPPLIED
SELZENTRY is available in 150-mg and 300-mg tablets.
Reference
1. Data on file. ViiV Healthcare Group of Companies. Research Triangle Park, NC.