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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 2 controlled studies of SELZENTRY in treatment-experienced patients and 1 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 on a current sample 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

BOXED 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 is contraindicated in patients with severe renal impairment (CrCl <30 mL/min) or end-stage renal disease (ESRD) 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 life-threatening events, has been reported in clinical trials and postmarketing. These events occurred approximately 1 month after patients started 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. 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 hepatitis B and/or C virus. 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. More cardiovascular events, including myocardial ischemia and/or infarction, were observed in treatment-experienced patients who received SELZENTRY compared to placebo. In treatment-naïve patients, the incidence of such events was lower with SELZENTRY than with efavirenz.

Caution should be used when administering SELZENTRY in patients with a history of, or risk factors for, postural hypotension, cardiovascular comorbidities, or who receive concomitant medication known to lower blood pressure. Patients with cardiovascular comorbidities could be at increased risk of cardiovascular adverse events triggered by postural hypotension. 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 is contraindicated in patients with severe renal impairment (CrCl <30 mL/min) or end-stage renal disease (ESRD) who are taking potent CYP3A inhibitors with or without a potent CYP3A inducer due to an increased risk of postural hypotension as a result of increased systemic exposure to SELZENTRY.

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

Treatment-experienced patients through 48 weeks

The most common adverse events (≥5%) reported in the MOTIVATE trials with SELZENTRY twice-daily therapy with frequency rates higher than placebo, regardless of causality, were upper respiratory tract infections (23% vs 13%), cough and associated symptoms (14% vs 5%), pyrexia (13% vs 9%), rash (11% vs 5%), dizziness/postural dizziness (9% vs 8%), herpes infection (8% vs 4%), appetite disorders (8% vs 7%), disturbances in initiating and maintaining sleep (8% vs 5%), sinusitis (7% vs 3%), bronchitis (7% vs 5%), joint-related signs and symptoms (7% vs 3%), constipation (6% vs 3%), upper respiratory tract signs and symptoms (6% vs 3%), bladder and urethral symptoms (5% vs 1%), paresthesias and dysesthesias (5% vs 3%), and apocrine and eccrine gland disorders (5% vs 4%).

Treatment-naïve patients through 96 weeks

The most common adverse events (≥5%) reported in the MERIT trial 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%), GI atonic and hypomotility disorders not elsewhere classified (NEC) (9% vs 5%), anemias NEC (8% vs 5%), herpes infection (7% vs 6%), bacterial infections NEC (6% vs 3%), joint-related signs and symptoms (6% vs 5%), nail and nail bed conditions (6% vs 2%), and herpes zoster/varicella (5% vs 4%).


CONCOMITANT USE

SELZENTRY is a substrate of CYP3A and P-glycoprotein (P-gp). Coadministration with potent CYP3A inhibitors, including delavirdine or protease inhibitors (except tipranavir/ritonavir), 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.


USE IN SPECIFIC PATIENT POPULATIONS

Pregnancy: Pregnancy Category B. SELZENTRY should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. An Antiretroviral Pregnancy Registry has been established. Please see Section 8.1 of the US Prescribing Information for SELZENTRY for additional information.

Nursing Mothers: The Centers for Disease Control and Prevention recommends that HIV-1–infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Because of both the potential for HIV transmission and the potential for adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving SELZENTRY.

Pediatric Patients: SELZENTRY should not be used in patients <18 years of age because the pharmacokinetics, safety and efficacy of this drug have not been established in this patient population.

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.


HOW SUPPLIED

SELZENTRY is available in 150-mg and 300-mg tablets.

IMPORTANT SAFETY INFORMATION

Important Safety Information.. continue reading

BOXED 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 is contraindicated in patients with severe renal impairment (CrCl <30 mL/min) or end-stage renal disease (ESRD) 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 life-threatening events, has been reported in clinical trials and postmarketing. These events occurred approximately 1 month after patients started 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. 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 hepatitis B and/or C virus. 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. More cardiovascular events, including myocardial ischemia and/or infarction, were observed in treatment-experienced patients who received SELZENTRY compared to placebo. In treatment-naive patients, the incidence of such events was lower with SELZENTRY than with efavirenz.

Caution should be used when administering SELZENTRY in patients with a history of, or risk factors for, postural hypotension, cardiovascular comorbidities, or who receive concomitant medication known to lower blood pressure. Patients with cardiovascular comorbidities could be at increased risk of cardiovascular adverse events triggered by postural hypotension. 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 is contraindicated in patients with severe renal impairment (CrCl <30 mL/min) or end-stage renal disease (ESRD) who are taking potent CYP3A inhibitors with or without a potent CYP3A inducer due to an increased risk of postural hypotension as a result of increased systemic exposure to SELZENTRY.

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

Treatment-experienced patients through 48 weeks

The most common adverse events (≥5%) reported in the MOTIVATE trials with SELZENTRY twice-daily therapy with frequency rates higher than placebo, regardless of causality, were upper respiratory tract infections (23% vs 13%), cough and associated symptoms (14% vs 5%), pyrexia (13% vs 9%), rash (11% vs 5%), dizziness/postural dizziness (9% vs 8%), herpes infection (8% vs 4%), appetite disorders (8% vs 7%), disturbances in initiating and maintaining sleep (8% vs 5%), sinusitis (7% vs 3%), bronchitis (7% vs 5%), joint-related signs and symptoms (7% vs 3%), constipation (6% vs 3%), upper respiratory tract signs and symptoms (6% vs 3%), bladder and urethral symptoms (5% vs 1%), paresthesias and dysesthesias (5% vs 3%), and apocrine and eccrine gland disorders (5% vs 4%).

Treatment-naïve patients through 96 weeks

The most common adverse events (≥5%) reported in the MERIT trial 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%), GI atonic and hypomotility disorders not elsewhere classified (NEC) (9% vs 5%), anemias NEC (8% vs 5%), herpes infection (7% vs 6%), bacterial infections NEC (6% vs 3%), joint-related signs and symptoms (6% vs 5%), nail and nail bed conditions (6% vs 2%), and herpes zoster/varicella (5% vs 4%).

CONCOMITANT USE

SELZENTRY is a substrate of CYP3A and P-glycoprotein (P-gp). Coadministration with potent CYP3A inhibitors, including delavirdine or protease inhibitors (except tipranavir/ritonavir), 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.

USE IN SPECIFIC PATIENT POPULATIONS

Pregnancy: Pregnancy Category B. SELZENTRY should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. An Antiretroviral Pregnancy Registry has been established. Please see Section 8.1 of the US Prescribing Information for SELZENTRY for additional information.

Nursing Mothers: The Centers for Disease Control and Prevention recommends that HIV-1–infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Because of both the potential for HIV transmission and the potential for adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving SELZENTRY.

Pediatric Patients: SELZENTRY should not be used in patients <18 years of age because the pharmacokinetics, safety and efficacy of this drug have not been established in this patient population.

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.

HOW SUPPLIED

SELZENTRY is available in 150-mg and 300-mg tablets.

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