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    Integrase Strand Transfer Inhibitor (INSTI)s

    DEA CLASS

    Rx

    DESCRIPTION

    First FDA-approved HIV integrase strand transfer inhibitor (HIV-1 INSTI)
    Used for treatment of HIV-1 infection in combination with other antiretrovirals
    Elevated CPK, muscle weakness, and rhabdomyolysis reported

    COMMON BRAND NAMES

    Isentress, Isentress HD

    HOW SUPPLIED

    Isentress Oral Gran F/Recon: 100mg
    Isentress Oral Tab Chew: 25mg, 100mg
    Isentress/Isentress HD Oral Tab: 400mg, 600mg

    DOSAGE & INDICATIONS

    For the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents.
    Oral dosage (400 mg film-coated tablet)

    NOTE: Due to differences in exposure observed between the formulations in clinical trials, the 400 mg film-coated tablet is the preferred formulation in pediatric patients weighing 25 kg or more; however, the chewable tablet may be used in patients who are unable to swallow the film-coated tablet. There are no data in pediatrics to guide dosage during coadministration with rifampin.

    Adults

    400 mg PO twice daily. During coadministration with rifampin, the recommended dosage is 800 mg PO twice daily.

    Children and Adolescents weighing 25 kg or more

    400 mg PO twice daily.

    Oral dosage (600 mg film-coated tablet)
    Adults

    1,200 mg (2 x 600 mg) PO once daily. The high dose regimen is indicated for treatment-naive patients or patients who are virologically suppressed on an initial regimen of 400 mg twice daily. Coadministration with rifampin is not recommended.

    Children and Adolescents weighing 40 kg or more

    1,200 mg (2 x 600 mg) PO once daily. The high dose (HD) regimen is indicated for treatment-naive patients or patients who are virologically suppressed on an initial regimen of 400 mg twice daily. Coadministration with rifampin is not recommended.[33530] Although the HD tablets are FDA-approved in pediatric patients weighing 40 kg or more, guidelines do not recommend use in patients weighing less than 50 kg as there are no clinical data on raltegravir HD once-daily dosing in this population.[42452]

    Oral dosage (chewable tablets)

    NOTE: Due to differences in exposure observed between the formulations in clinical trials, the 400 mg film-coated tablet is the preferred formulation in pediatric patients weighing 25 kg or more; however, the chewable tablet may be used in patients who are unable to swallow the film-coated tablet. There are no data in pediatrics to guide dosage during coadministration with rifampin.

    Children and Adolescents weighing 40 kg or more

    300 mg PO twice daily.

    Children and Adolescents weighing 28 to 39 kg

    200 mg PO twice daily.

    Children weighing 20 to 27 kg

    150 mg PO twice daily.

    Children weighing 14 to 19 kg

    100 mg PO twice daily.

    Children weighing 11 to 13 kg

    75 mg PO twice daily.

    Oral dosage (powder for suspension)

    NOTE: There are no data in pediatrics to guide dosage during coadministration with rifampin.

    Children weighing 14 to 19 kg

    100 mg (10 mL) PO twice daily.

    Infants and Children 4 weeks and older weighing 11 to 13 kg

    80 mg (8 mL) PO twice daily.

    Infants and Children 4 weeks and older weighing 8 to 10 kg

    60 mg (6 mL) PO twice daily.

    Infants and Children 4 weeks and older weighing 6 to 7 kg

    40 mg (4 mL) PO twice daily.

    Infants 4 weeks and older weighing 4 to 5 kg

    30 mg (3 mL) PO twice daily.

    Infants 4 weeks and older weighing 3 kg

    25 mg (2.5 mL) PO twice daily.

    Term Neonates older than 7 days weighing 4 kg

    15 mg (1.5 mL) PO twice daily (approximately 3 mg/kg/dose).

    Term Neonates older than 7 days weighing 3 kg

    10 mg (1 mL) PO twice daily (approximately 3 mg/kg/dose).

    Term Neonates older than 7 days weighing 2 kg

    8 mg (0.8 mL) PO twice daily (approximately 3 mg/kg/dose).

    Term Neonates 0 to 7 days weighing 4 kg

    7 mg (0.7 mL) PO once daily (approximately 1.5 mg/kg/dose). If the mother has taken raltegravir 2 to 24 hours before delivery, administer the neonate's first dose 24 to 48 hours after birth.

    Term Neonates 0 to 7 days weighing 3 kg

    5 mg (0.5 mL) PO once daily (approximately 1.5 mg/kg/dose). If the mother has taken raltegravir 2 to 24 hours before delivery, administer the neonate's first dose 24 to 48 hours after birth.

    Term Neonates 0 to 7 days weighing 2 kg

    4 mg (0.4 mL) PO once daily (approximately 1.5 mg/kg/dose). If the mother has taken raltegravir 2 to 24 hours before delivery, administer the neonate's first dose 24 to 48 hours after birth.

    For human immunodeficiency virus (HIV) prophylaxis†.
    For human immunodeficiency virus (HIV) prophylaxis† after occupational exposure.
    Oral dosage (film-coated tablets)
    Adults

    400 mg PO twice daily in combination with tenofovir and either emtricitabine or lamivudine for 28 days are preferred HIV post-exposure prophylaxis (PEP) regimens. A 3-drug regimen is recommended; however, the use of a 2-drug regimen would be preferred to discontinuing prophylaxis completely if tolerability is a concern. Begin prophylaxis as soon as possible, ideally within 2 hours of exposure. If initiation of prophylaxis is delayed (beyond 36 hours or 72 hours after exposure), efficacy of the antiretroviral regimen may be diminished and treatment should be determined on a case-by-case basis. Exposures for which PEP is indicated include: skin puncture by a sharp object that has been contaminated with blood, body fluid, or other infectious material; bite from a patient with visible bleeding in the mouth which causes bleeding by the exposed worker; splash of blood, body fluid, or other infectious material onto the workers mouth, nose, or eyes; exposure of blood, body fluid, or other infectious material on a workers non-intact skin (i.e., open wound, chapped skin, abrasion, dermatitis).

    For human immunodeficiency virus (HIV) prophylaxis† after nonoccupational exposure, including sexual assault.
    NOTE: Higher risk exposures for which prophylaxis is recommended include exposure of vagina, rectum, eye, mouth, or other mucous membrane, nonintact skin, or percutaneous contact with blood, semen, vaginal secretions, rectal secretions, breast milk, or any body fluid that is visibly contaminated with blood when the source is known to be HIV-positive. Exposures to a source patient with unknown HIV status should be assessed on a case-by-case basis.
    Oral dosage (film-coated tablets)
    Adults

    400 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is a preferred HIV post-exposure prophylaxis (PEP) regimen in adults. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.

    Children and Adolescents weighing 25 kg or more

    400 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is a preferred HIV post-exposure prophylaxis (PEP) regimen in children and adolescents weighing 25 kg or more. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.

    Oral dosage (chewable tablets)
    Children 2 to 12 years weighing 40 kg or more

    300 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is a preferred HIV post-exposure prophylaxis (PEP) regimen in children 2 years and older. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.

    Children 2 to 12 years weighing 28 to 39 kg

    200 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is a preferred HIV post-exposure prophylaxis (PEP) regimen in children 2 years and older. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.

    Children 2 to 12 years weighing 20 to 27 kg

    150 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is a preferred HIV post-exposure prophylaxis (PEP) regimen in children 2 years and older. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.

    Children 2 to 12 years weighing 14 to 19 kg

    100 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is a preferred HIV post-exposure prophylaxis (PEP) regimen in children 2 years and older. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.

    Children 2 to 12 years weighing 11 to 13 kg

    75 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is a preferred HIV post-exposure prophylaxis (PEP) regimen in children 2 years and older. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.

    For perinatal human immunodeficiency virus (HIV) prophylaxis† in neonates at high risk for HIV acquisition.
    NOTE: Presumptive therapy with a 3-drug combination antiretroviral (ARV) regimen, consisting of zidovudine, lamivudine, and raltegravir at treatment doses, is a treatment option recommended for neonates with presumed HIV exposure (mothers with unknown HIV status who test HIV positive at delivery or postpartum or whose newborns have a positive HIV antibody test) or those at high risk for perinatal HIV transmission (neonates born to HIV-infected mothers: who have not received antepartum or intrapartum ARV treatment, who have received only intrapartum ARV treatment, who have suboptimal viral suppression (confirmed HIV RNA of 50 copies/mL or more) near delivery (within 4 weeks of delivery), who have acute or primary HIV infection during pregnancy or breastfeeding, or who have known ARV drug-resistant virus).[23512]
    Oral dosage (powder for suspension)
    Infants 4 to 6 weeks weighing 6 to 7 kg

    40 mg (4 mL) PO twice daily (approximately 6 mg/kg/dose) in combination with zidovudine and lamivudine. The optimal duration of presumptive HIV therapy in high-risk infants is unknown. A 6-week course of zidovudine is recommended. For raltegravir and lamivudine, a treatment duration of 2 to 6 weeks is recommended. The recommended duration for these drugs varies based on HIV nucleic acid test (NAT) results, maternal viral load at the time of delivery, and additional risk factors for HIV transmission. Consultation with an expert in pediatric HIV is recommended when selecting a therapy duration, as this decision should be based on patient-specific risk factors and interim HIV NAT results.[23512]

    Infants 4 to 6 weeks weighing 4 to 5 kg

    30 mg (3 mL) PO twice daily (approximately 6 mg/kg/dose) in combination with zidovudine and lamivudine. The optimal duration of presumptive HIV therapy in high-risk infants is unknown. A 6-week course of zidovudine is recommended. For raltegravir and lamivudine, a treatment duration of 2 to 6 weeks is recommended. The recommended duration for these drugs varies based on HIV nucleic acid test (NAT) results, maternal viral load at the time of delivery, and additional risk factors for HIV transmission. Consultation with an expert in pediatric HIV is recommended when selecting a therapy duration, as this decision should be based on patient-specific risk factors and interim HIV NAT results.[23512]

    Infants 4 to 6 weeks weighing 3 kg

    25 mg (2.5 mL) PO twice daily (approximately 6 mg/kg/dose) in combination with zidovudine and lamivudine. The optimal duration of presumptive HIV therapy in high-risk infants is unknown. A 6-week course of zidovudine is recommended. For raltegravir and lamivudine, a treatment duration of 2 to 6 weeks is recommended. The recommended duration for these drugs varies based on HIV nucleic acid test (NAT) results, maternal viral load at the time of delivery, and additional risk factors for HIV transmission. Consultation with an expert in pediatric HIV is recommended when selecting a therapy duration, as this decision should be based on patient-specific risk factors and interim HIV NAT results.[23512]

    Term Neonates older than 7 days weighing 4 kg

    15 mg (1.5 mL) PO twice daily (approximately 3 mg/kg/dose) in combination with zidovudine and lamivudine. The optimal duration of presumptive HIV therapy in high-risk infants is unknown. A 6-week course of zidovudine is recommended. For raltegravir and lamivudine, a treatment duration of 2 to 6 weeks is recommended. The recommended duration for these drugs varies based on HIV nucleic acid test (NAT) results, maternal viral load at the time of delivery, and additional risk factors for HIV transmission. Consultation with an expert in pediatric HIV is recommended when selecting a therapy duration, as this decision should be based on patient-specific risk factors and interim HIV NAT results.[23512]

    Term Neonates older than 7 days weighing 3 kg

    10 mg (1 mL) PO twice daily (approximately 3 mg/kg/dose) in combination with zidovudine and lamivudine. The optimal duration of presumptive HIV therapy in high-risk infants is unknown. A 6-week course of zidovudine is recommended. For raltegravir and lamivudine, a treatment duration of 2 to 6 weeks is recommended. The recommended duration for these drugs varies based on HIV nucleic acid test (NAT) results, maternal viral load at the time of delivery, and additional risk factors for HIV transmission. Consultation with an expert in pediatric HIV is recommended when selecting a therapy duration, as this decision should be based on patient-specific risk factors and interim HIV NAT results.[23512]

    Term Neonates older than 7 days weighing 2 kg

    8 mg (0.8 mL) PO twice daily (approximately 3 mg/kg/dose) in combination with zidovudine and lamivudine. The optimal duration of presumptive HIV therapy in high-risk infants is unknown. A 6-week course of zidovudine is recommended. For raltegravir and lamivudine, a treatment duration of 2 to 6 weeks is recommended. The recommended duration for these drugs varies based on HIV nucleic acid test (NAT) results, maternal viral load at the time of delivery, and additional risk factors for HIV transmission. Consultation with an expert in pediatric HIV is recommended when selecting a therapy duration, as this decision should be based on patient-specific risk factors and interim HIV NAT results.[23512]

    Term Neonates 0 to 7 days weighing 4 kg

    7 mg (0.7 mL) PO once daily (approximately 1.5 mg/kg/dose) in combination with zidovudine and lamivudine. Initiate treatment as close to the time of birth as possible, preferably within 6 hours of delivery. However, if the mother has taken raltegravir 2 to 24 hours prior to delivery, delay the neonate's first dose of raltegravir until 24 to 48 hours after birth; zidovudine and lamivudine should still be started as soon as possible. The optimal duration of presumptive HIV therapy in high-risk infants is unknown. A 6-week course of zidovudine is recommended. For raltegravir and lamivudine, a treatment duration of 2 to 6 weeks is recommended. The recommended duration for these drugs varies based on HIV nucleic acid test (NAT) results, maternal viral load at the time of delivery, and additional risk factors for HIV transmission. Consultation with an expert in pediatric HIV is recommended when selecting a therapy duration, as this decision should be based on patient-specific risk factors and interim HIV NAT results.[23512]

    Term Neonates 0 to 7 days weighing 3 kg

    5 mg (0.5 mL) PO once daily (approximately 1.5 mg/kg/dose) in combination with zidovudine and lamivudine. Initiate treatment as close to the time of birth as possible, preferably within 6 hours of delivery. However, if the mother has taken raltegravir 2 to 24 hours prior to delivery, delay the neonate's first dose of raltegravir until 24 to 48 hours after birth; zidovudine and lamivudine should still be started as soon as possible. The optimal duration of presumptive HIV therapy in high-risk infants is unknown. A 6-week course of zidovudine is recommended. For raltegravir and lamivudine, a treatment duration of 2 to 6 weeks is recommended. The recommended duration for these drugs varies based on HIV nucleic acid test (NAT) results, maternal viral load at the time of delivery, and additional risk factors for HIV transmission. Consultation with an expert in pediatric HIV is recommended when selecting a therapy duration, as this decision should be based on patient-specific risk factors and interim HIV NAT results.[23512]

    Term Neonates 0 to 7 days weighing 2 kg

    4 mg (0.4 mL) PO once daily (approximately 1.5 mg/kg/dose) in combination with zidovudine and lamivudine. Initiate treatment as close to the time of birth as possible, preferably within 6 hours of delivery. However, if the mother has taken raltegravir 2 to 24 hours prior to delivery, delay the neonate's first dose of raltegravir until 24 to 48 hours after birth; zidovudine and lamivudine should still be started as soon as possible. The optimal duration of presumptive HIV therapy in high-risk infants is unknown. A 6-week course of zidovudine is recommended. For raltegravir and lamivudine, a treatment duration of 2 to 6 weeks is recommended. The recommended duration for these drugs varies based on HIV nucleic acid test (NAT) results, maternal viral load at the time of delivery, and additional risk factors for HIV transmission. Consultation with an expert in pediatric HIV is recommended when selecting a therapy duration, as this decision should be based on patient-specific risk factors and interim HIV NAT results.[23512]

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    800 mg/day PO for the 400 mg film-coated tablet; 1,600 mg/day PO with concomitant rifampin; 1,200 mg/day for the 600 mg film-coated tablet; safety and efficacy of other formulations have not been established.

    Geriatric

    800 mg/day PO for the 400 mg film-coated tablet; 1,600 mg/day PO with concomitant rifampin; 1,200 mg/day for the 600 mg film-coated tablet; safety and efficacy of other formulations have not been established.

    Adolescents

    weight 40 kg or more: 600 mg/day PO for the chewable tablet; 800 mg/day PO for the 400 mg film-coated tablet; 1,200 mg/day for the 600 mg film-coated tablet; safety and efficacy have not been established for the oral suspension.
    weight 28 to 39 kg: 400 mg/day PO for the chewable tablet; 800 mg/day PO for the 400 mg film-coated tablet; safety and efficacy of other formulations have not been established.

    Children

    weight 40 kg or more: 600 mg/day PO for the chewable tablet; 800 mg/day PO for the 400 mg film-coated tablet; 1,200 mg/day for the 600 mg film-coated tablet; safety and efficacy have not been established for the oral suspension.
    weight 28 to 39 kg: 400 mg/day PO for the chewable tablet; 800 mg/day PO for the 400 mg film-coated tablet; safety and efficacy of other formulations have not been established.
    weight 25 to 27 kg: 300 mg/day PO for the chewable tablet; 800 mg/day PO for the 400 mg film-coated tablet; safety and efficacy of other formulations have not been established.
    weight 20 to 24 kg: 300 mg/day PO for the chewable tablet; safety and efficacy of other formulations have not been established.
    weight 14 to 19 kg: 200 mg/day PO for the oral suspension or chewable tablet; safety and efficacy have not been established for the film-coated tablets.
    weight 11 to 13 kg: 160 mg/day PO for the oral suspension; 150 mg/day PO for the chewable tablet; safety and efficacy have not been established for the film-coated tablets.
    weight 8 to 10 kg: 120 mg/day PO for the oral suspension; safety and efficacy of other formulations have not been established.

    Infants

    weight 11 to 13 kg: 160 mg/day PO for the oral suspension; 150 mg/day PO for the chewable tablet; safety and efficacy have not been established for the film-coated tablets.
    weight 8 to 10 kg: 120 mg/day PO for the oral suspension; safety and efficacy of other formulations have not been established.
    weight 6 to 7 kg: 80 mg/day PO for the oral suspension; safety and efficacy of other formulations have not been established.
    weight 4 to 5 kg: 60 mg/day PO for the oral suspension; safety and efficacy of other formulations have not been established.
    weight 3 kg: 50 mg/day PO for the oral suspension; safety and efficacy of other formulations have not been established.

    Neonates

    Term Neonates 8 days and older weighing 4 kg: 30 mg/day PO for the oral suspension; safety and efficacy of other formulations have not been established.
    Term Neonates 8 days and older weighing 3 kg: 20 mg/day PO for the oral suspension; safety and efficacy of other formulations have not been established.
    Term Neonates 8 days and older weighing 2 kg: 16 mg/day PO for the oral suspension; safety and efficacy of other formulations have not been established.
    Term Neonates 0 to 7 days weighing 4 kg: 7 mg/day PO for the oral suspension; safety and efficacy of other formulations have not been established.
    Term Neonates 0 to 7 days weighing 3 kg: 5 mg/day PO for the oral suspension; safety and efficacy of other formulations have not been established.
    Term Neonates 0 to 7 days weighing 2 kg: 4 mg/day PO for the oral suspension; safety and efficacy of other formulations have not been established.
    Premature and Term Neonates weighing less than 2 kg: Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    The 600 mg tablet is not recommended for use in patients with any degree of hepatic impairment as studies have not been conducted. For the other formulations, no dosage adjustment is necessary for patients with mild to moderate hepatic impairment; caution is advised for patients with severe hepatic impairment as studies have not been conducted.

    Renal Impairment

    No dosage adjustment is necessary in patients with renal impairment; however, because the extent to which raltegravir may be dialyzable is unknown, dosing before a dialysis session should be avoided.

    ADMINISTRATION

    Oral Administration

    NOTE: The 400 mg and 600 mg film-coated tablets are not bioequivalent to the chewable tablets or powder for oral suspension. Do NOT substitute the chewable tablets or powder for oral suspension for the film-coated tablets, or vice versa.
    Administer with or without food.

    Oral Solid Formulations

    Film-coated tablets: Do not cut, crush, or chew; swallow whole.
    Chewable tablets: May be chewed or swallowed whole. The 100-mg chewable tablet can be divided into equal halves. For pediatric patients who have difficulty swallowing, the 25-mg chewable tablet may be crushed and administered in liquid.
    Preparation of crushed 25-mg chewable tablet
    Place the tablet(s) in a small, clean cup. For each tablet, add approximately 5 mL of liquid (e.g., water, juice, or breast milk).
    Within 2 minutes, the tablet(s) will absorb the liquid and fall apart.
    Using a spoon, crush any remaining pieces of the tablet(s). Immediately administer the entire dose orally.
    If any portion of the dose is left in the cup, add approximately 5 mL of liquid, swirl, and administer immediately.[33530]

    Oral Liquid Formulations

    Powder for oral suspension
    Each single-use packet contains 100 mg of raltegravir.
    Using the provided mixing cup, combine 10 mL of water and the entire contents of 1 packet and mix (final concentration 10 mg/mL). Gently swirl the mixing cup for 45 seconds in a circular motion to mix the suspension; do NOT shake.
    Calculate the required volume of the 10 mg/mL suspension for the prescribed dose.
    Measure and administer the dose using an oral syringe. The dose should be administered orally within 30 minutes of mixing.
    Discard any remaining suspension.

    STORAGE

    Isentress:
    - Discard reconstituted product if not used within 30 minutes
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in original package until time of use
    Isentress HD:
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Unplanned antiretroviral therapy interruption may be necessary for specific situations, such as serious drug toxicity, intercurrent illness or surgery precluding oral intake (e.g., gastroenteritis or pancreatitis), severe hyperemesis gravidarum unresponsive to antiemetics, or drug non-availability. If short-term treatment interruption (i.e., less than 1 to 2 days) is necessary, in general, it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption occurs in a pregnant patient or is because of a serious toxicity. However, if a short-term treatment interruption is anticipated in the case of elective surgery, the pharmacokinetic properties and food requirements of specific drugs should be considered; as stopping all simultaneously in a regimen containing drugs with differing half-lives may result in functional monotherapy of the drug with the longest half-life and may increase the risk for resistant mutations. Health care providers are advised to reinitiate a complete and effective antiretroviral regimen as soon as possible after an interruption of therapy. Planned long-term treatment interruptions are not recommended due to the potential for HIV disease progression (i.e., declining CD4 counts, viral rebound, acute viral syndrome), development of minor HIV-associated manifestations or serious non-AIDS complications, development of drug resistance, increased risk of HIV transmission, and increased risk for opportunistic infections. If therapy must be discontinued, counsel patient on the potential risks and closely monitor for any clinical or laboratory abnormalities. [46638] [42452]

    Breast-feeding

    To reduce the risk of postnatal transmission, mothers with HIV within the United States are advised by the Centers for Disease Control and Prevention to avoid breast-feeding. This recommendation applies to both untreated women and women who are receiving antiretroviral therapy, including raltegravir. If a mother with HIV opts to breast-feed, the infant should undergo immediate diagnostic and virologic HIV testing. Testing should continue throughout breast-feeding and up to 6 months after cessation of breast-feeding. For expert consultation, health care workers may contact the Perinatal HIV Hotline (888-448-8765).[42452] There are no data on the presence of raltegravir in human milk, the effects on the breastfed infant, or the effects on the milk production. Antiretroviral medications whose passage into human breast milk have been evaluated include nevirapine, zidovudine, lamivudine, and nelfinavir.

    Human immunodeficiency virus (HIV) infection resistance

    Testing for human immunodeficiency virus (HIV) infection resistance is recommended in all antiretroviral treatment-naive patients at the time of HIV diagnosis, regardless of whether treatment will be initiated. Additionally, perform resistance testing prior to initiating or changing any HIV treatment regimen. Transmission of drug-resistant HIV strains has been both well documented and associated with suboptimal virologic response to initial antiretroviral therapy. In high-income countries (e.g., US, some European countries, Australia, Japan), approximately 10% to 17% of treatment-naive individuals have resistance mutations to at least 1 antiretroviral drug; up to 8% (but generally less than 5%) of transmitted viruses will exhibit resistance to drugs from more than 1 class. Therefore, resistance testing at baseline can help optimize treatment and, thus, virologic response. In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but may still increase the risk of treatment failure when therapy is eventually initiated. Thus, if therapy is deferred, resistance testing should still be performed during acute HIV infection with the genotypic resistance test result kept in the patient's medical record until it becomes clinically useful. Additionally, because of the possibility of acquisition of another drug-resistant virus before treatment initiation, repeat resistance testing at the time therapy is initiated would be prudent.

    Hepatic disease, hepatitis, hepatitis B and HIV coinfection, hepatitis C and HIV coinfection

    Raltegravir is metabolized by the liver. Studies regarding the use of the 600 mg tablet formulation in patients with hepatic impairment have not been conducted; therefore, this formulation is not recommended for use in patients with any degree of hepatic impairment. For the other formulations, no dosage adjustment is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetic parameters has not been studied; caution is needed when administering raltegravir to patients with severe hepatic disease. Cautious administration is also recommended for patients with hepatitis. In general, the safety profile in subjects with hepatitis B or hepatitis C virus coinfection is similar to subjects without hepatitis B or hepatitis C virus coinfection. However, as compared with data from patients without hepatitis, a higher percentage of patients with chronic, active hepatitis B or C and baseline liver function tests not greater than 5-times the upper limit of normal had elevated AST, ALT, or total bilirubin.[33530] Hyperbilirubinemia has been observed in HIV-exposed infants receiving raltegravir through 6 weeks of life. In the IMPAACT P1110 study, grade 3 to 4 levels of increased bilirubin were reported in 3 of 52 infants. However, no bilirubin concentrations exceeded 16 mg/dL, and no infants required phototherapy or other clinical treatment for hyperbilirubinemia. Raltegravir at extremely high concentrations may displace unconjugated bilirubin from albumin, increasing the potential risk of bilirubin-induced neurologic dysfunction. Due to the possible risk of hyperbilirubinemia, consider serum total and direct bilirubin measurement in infants receiving raltegravir. HIV treatment guidelines recommend all patients presenting with HIV infection undergo testing for hepatitis C, with continued annual screening advised for those persons considered high risk for acquiring hepatitis C. If hepatitis C and HIV coinfection is identified, consider treating both viral infections concurrently. For most patients, the benefits of concurrent therapy outweigh the potential risks (i.e., drug-induced hepatic injury, complex drug interactions, overlapping toxicities); therefore, it is recommended to initiate a fully suppressive antiretroviral (ARV) therapy and a hepatitis C regimen in all coinfected patients regardless of CD4 count. However, for antiretroviral-naive patients with CD4 counts greater than 500 cells/mm3, consideration may be given to deferring ARV until the hepatitis C treatment regimen has been completed. Conversely, for patients with CD4 counts less than 200 cells/mm3, consider delaying initiation of the hepatitis C treatment regimen until the patient is stable on a fully suppressive ARV regimen. Patients presenting with HIV infection should also be screened for hepatitis B virus (HBV) coinfection to assure appropriate treatment. Patients with hepatitis B and HIV coinfection should be started on a fully suppressive ARV with activity against both viruses (regardless of CD4 counts and HBV DNA concentrations). HIV treatment guidelines recommend these patients receive an ARV regimen that contains a dual NRTI backbone of tenofovir alafenamide or tenofovir disoproxil fumarate with either emtricitabine or lamivudine. If tenofovir cannot be used, entecavir should be used in combination with a fully suppressive ARV regimen (note: entecavir should not be considered part of the ARV regimen). Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, tenofovir, or entecavir as the only active agent) as this may result in HIV resistant strains. Further, HBV treatment regimens that include adefovir or telbivudine should also be avoided, as these regimens are associated with a higher incidence of toxicities and increased rates of HBV treatment failure. Most coinfected patients should continue treatment indefinitely with the goal of maximal HIV suppression and prevention of HBV relapse. If treatment must be discontinued, monitor transaminase concentrations every 6 weeks for the first 3 months, and every 3 to 6 months thereafter. For patients who refuse a fully suppressive ARV regimen, but still require treatment for HBV, consider 48 weeks of peginterferon alfa; do not administer HIV-active medications in the absence of a fully suppressive ARV regimen. Instruct hepatitis and HIV coinfected patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate. [33530] [34362] [46638]

    Pregnancy

    Antiretroviral therapy should be provided to all women during pregnancy, regardless of HIV RNA concentrations or CD4 cell count. Using highly active antiretroviral combination therapy (HAART) to maximally suppress viral replication is the most effective strategy to prevent the development of resistance and to minimize the risk of perinatal transmission. In treatment-naive women, begin HAART as soon as pregnancy is recognized or HIV is diagnosed, without waiting for the results of resistance testing; subsequent modifications to the treatment regimen should be made once the test results are available. Women who are currently receiving antiretroviral treatment when pregnancy is recognized should continue their treatment regimen if it is currently effective in suppressing viral replication; consider resistance testing if HIV RNA concentrations are more than 500 copies/mL. For women not currently receiving HAART, but who have previously received treatment, obtain a complete and accurate history of all prior antiretroviral regimens used and results of prior resistance testing, and perform resistance testing if HIV RNA concentrations are more than 500 copies/mL; treatment should be initiated prior to receiving resistance test results. HIV guidelines recommend raltegravir, administered via twice-daily dosing, as a preferred treatment option for use in pregnant women. In addition, because of its ability to rapidly suppress viral load (approximately 2-log copies/mL decrease after 2 weeks of treatment), raltegravir may be a preferred option for use late in pregnancy in women with high viral loads. For non-pregnant women who are trying to conceive, raltegravir may be considered as a preferred option as no cases of neural tube defects (a birth defect associated with use of another integrase inhibitor) have been reported following use of raltegravir around the time of conception. Available data from the Antiretroviral Pregnancy Registry (APR), which includes over 480 first trimester exposures to raltegravir, have shown no difference in the risk of overall major birth defects when compared to the 2.7% background rate among pregnant women in the US. The prevalence of birth defects was 3.1% (95% CI: 1.7% to 5%) when exposure occurred in the first trimester. Supplemental data from the APR regarding central nervous system birth defects are available. Among the reported exposures to raltegravir (327 periconception, 95 late first trimester, 399 second/third trimester), 1 central nervous system birth defect was identified during the last first trimester; however, this was not a neural tube or encephalocele defect. Regular laboratory monitoring is recommended to determine antiretroviral efficacy. Monitor CD4 counts at the initial visit. Women who have been on HAART for at least 2 years and have consistent viral suppression and CD4 counts consistently greater than 300 cells/mm3 do not need CD4 counts monitored after the initial visit during the pregnancy. However, CD4 counts should be monitored every 3 months during pregnancy for women on HAART less than 2 years, women with CD4 count less than 300 cells/mm3, or women with inconsistent adherence or detectable viral loads. Monitor plasma HIV RNA at the initial visit, 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, then at least every 3 months during pregnancy, and at 34 to 36 weeks gestation. Perform antiretroviral resistance assay (genotypic testing, and if indicated, phenotypic testing) at baseline in all women with HIV RNA concentrations more than 500 copies/mL, unless they have already been tested for resistance. First trimester ultrasound is recommended to confirm gestational age and provide an accurate estimation of gestational age at delivery. A second trimester ultrasound can be used for both anatomical survey and determination of gestational age in those patients not seen until later in gestation. Perform standard glucose screening in women receiving antiretroviral therapy at 24 to 28 weeks gestation, although it should be noted that some experts would perform earlier screening with ongoing chronic protease inhibitor-based therapy initiated prior to pregnancy, similar to recommendations for women with high-risk factors for glucose intolerance. Liver function testing is recommended within 2 to 4 weeks after initiating or changing antiretroviral therapy, and approximately every 3 months thereafter during pregnancy (or as needed). All pregnant women should be counseled about the importance of adherence to their antiretroviral regimen to reduce the potential for development of resistance and perinatal transmission. It is strongly recommended that antiretroviral therapy, once initiated, not be discontinued. If a woman decides to discontinue therapy, a consultation with an HIV specialist is recommended. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to raltegravir; information about the registry can be obtained at www.apregistry.com or by calling 1-800-258-4263.[27468] [23512] [33530] [46638]

    Lactase deficiency, phenylketonuria

    Each film-coated raltegravir tablet contains lactose; patients with lactase deficiency should take appropriate precautions with use. Advise patients with phenylketonuria that the 25 mg and 100 mg chewable tablets contain approximately 0.05 mg and 0.1 mg, respectively, of phenylalanine. Phenylalanine, a component of aspartame, may be harmful to patients with phenylketonuria.

    Geriatric

    Clinical studies of raltegravir did not include sufficient numbers of patients aged 65 years or over to determine whether they respond differently from younger patients. In general, dose selection for a geriatric patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

    Depression, suicidal ideation

    It may be prudent to use raltegravir with caution in patients with a history of psychiatric disease, including depression or suicidal ideation. Both depression and suicidal ideation and behaviors have been noted in post-marketing reports, particularly in patients with a preexisting history of psychiatric disease.

    Autoimmune disease, Graves' disease, Guillain-Barre syndrome, immune reconstitution syndrome

    Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of HIV treatment, patients whose immune system responds to raltegravir therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as progressive multifocal leukoencephalopathy (PML), mycobacterium avium complex (MAC), cytomegalovirus (CMV), Pneumocystis pneumonia (PCP), or tuberculosis (TB)), which may necessitate further evaluation and treatment. In addition, autoimmune disease (including Graves' disease, Guillain-Barre syndrome, and polymyositis) may also develop; the time to onset is variable and may occur months after treatment initiation.

    Serious rash

    Patients receiving raltegravir may be at increased risk of developing serious rash. According to the manufacturer, fatal skin reactions (e.g., Stevens-Johnson Syndrome, toxic epidermal necrolysis) have been reported during the post-marketing period. Cases of hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction have also been reported. Health care providers are advised to closely monitor the clinical status patients during treatment. Immediately discontinue raltegravir and initiate appropriate therapy in any patient who develops signs of severe skin reactions, such as severe rash or rash accompanied with fever, fatigue, general malaise, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, facial edema, angioedema, or eosinophilia. Failure to promptly discontinue raltegravir therapy may result in a life-threatening reaction.

    Black patients, females, Hispanic patients

    Starting an integrase inhibitor-containing regimen (such as raltegravir) in treatment-naive patients has been associated with weight gain. Predictors and mechanisms for the increase in weight are still unclear; however, the weight gain appears to disproportionately affect females, Hispanic patients, and Black patients (particularly Black women). It is unknown whether the increase in weight is associated with significant cardio-metabolic risks or if it is reversible upon treatment discontinuation.

    ADVERSE REACTIONS

    Severe

    renal failure (unspecified) / Delayed / 0-2.0
    suicidal ideation / Delayed / 0-2.0
    rhabdomyolysis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known

    Moderate

    elevated hepatic enzymes / Delayed / 3.0-44.0
    hyperbilirubinemia / Delayed / 2.0-17.0
    hyperglycemia / Delayed / 2.0-10.0
    neutropenia / Delayed / 1.0-4.0
    hyperamylasemia / Delayed / 0-4.0
    gastritis / Delayed / 0-2.0
    nephrolithiasis / Delayed / 0-2.0
    hepatitis / Delayed / 0-2.0
    depression / Delayed / 0-2.0
    anemia / Delayed / 0-1.0
    thrombocytopenia / Delayed / 0-1.0
    myopathy / Delayed / Incidence not known
    conjunctivitis / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    oral ulceration / Delayed / Incidence not known

    Mild

    headache / Early / 2.0-4.0
    insomnia / Early / 4.0-4.0
    nausea / Early / 3.0-3.0
    vomiting / Early / 0-2.0
    abdominal pain / Early / 0-2.0
    dyspepsia / Early / 0-2.0
    dizziness / Early / 2.0-2.0
    fatigue / Early / 2.0-2.0
    asthenia / Delayed / 0-2.0
    infection / Delayed / 0-2.0
    diarrhea / Early / Incidence not known
    weight gain / Delayed / Incidence not known
    anxiety / Delayed / Incidence not known
    paranoia / Early / Incidence not known
    myalgia / Early / Incidence not known
    arthralgia / Delayed / Incidence not known
    malaise / Early / Incidence not known
    fever / Early / Incidence not known
    rash / Early / Incidence not known

    DRUG INTERACTIONS

    Aluminum Hydroxide: (Major) Coadministration or staggered administration of aluminum and/or magnesium-containing antacids is not recommended during treatment with raltegravir. Coadministration may result in decreased plasma concentrations of raltegravir, which may lead to HIV treatment failure or the development of viral resistance. In a drug interaction study, the AUC for raltegravir was decreased by 49% (90% CI, 35% to 60%), 51% (90% CI, 33% to 65%), and 30% (90% CI, 4% to 50%), when administered with, 2 hours before, and 2 hours after aluminum/magnesium hydroxide antacids, respectively.
    Aluminum Hydroxide; Magnesium Carbonate: (Major) Coadministration or staggered administration of aluminum and/or magnesium-containing antacids is not recommended during treatment with raltegravir. Coadministration may result in decreased plasma concentrations of raltegravir, which may lead to HIV treatment failure or the development of viral resistance. In a drug interaction study, the AUC for raltegravir was decreased by 49% (90% CI, 35% to 60%), 51% (90% CI, 33% to 65%), and 30% (90% CI, 4% to 50%), when administered with, 2 hours before, and 2 hours after aluminum/magnesium hydroxide antacids, respectively.
    Aluminum Hydroxide; Magnesium Hydroxide: (Major) Coadministration or staggered administration of aluminum and/or magnesium-containing antacids is not recommended during treatment with raltegravir. Coadministration may result in decreased plasma concentrations of raltegravir, which may lead to HIV treatment failure or the development of viral resistance. In a drug interaction study, the AUC for raltegravir was decreased by 49% (90% CI, 35% to 60%), 51% (90% CI, 33% to 65%), and 30% (90% CI, 4% to 50%), when administered with, 2 hours before, and 2 hours after aluminum/magnesium hydroxide antacids, respectively.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Major) Coadministration or staggered administration of aluminum and/or magnesium-containing antacids is not recommended during treatment with raltegravir. Coadministration may result in decreased plasma concentrations of raltegravir, which may lead to HIV treatment failure or the development of viral resistance. In a drug interaction study, the AUC for raltegravir was decreased by 49% (90% CI, 35% to 60%), 51% (90% CI, 33% to 65%), and 30% (90% CI, 4% to 50%), when administered with, 2 hours before, and 2 hours after aluminum/magnesium hydroxide antacids, respectively.
    Aluminum Hydroxide; Magnesium Trisilicate: (Major) Coadministration or staggered administration of aluminum and/or magnesium-containing antacids is not recommended during treatment with raltegravir. Coadministration may result in decreased plasma concentrations of raltegravir, which may lead to HIV treatment failure or the development of viral resistance. In a drug interaction study, the AUC for raltegravir was decreased by 49% (90% CI, 35% to 60%), 51% (90% CI, 33% to 65%), and 30% (90% CI, 4% to 50%), when administered with, 2 hours before, and 2 hours after aluminum/magnesium hydroxide antacids, respectively.
    Amlodipine; Atorvastatin: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
    Antacids: (Major) Coadministration or staggered administration of aluminum and/or magnesium-containing antacids is not recommended during treatment with raltegravir. Coadministration may result in decreased plasma concentrations of raltegravir, which may lead to HIV treatment failure or the development of viral resistance. In a drug interaction study, the AUC for raltegravir was decreased by 49% (90% CI, 35% to 60%), 51% (90% CI, 33% to 65%), and 30% (90% CI, 4% to 50%), when administered with, 2 hours before, and 2 hours after aluminum/magnesium hydroxide antacids, respectively.
    Aspirin, ASA; Pravastatin: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
    Atorvastatin: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
    Atorvastatin; Ezetimibe: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Coadministration of phenobarbital with raltegravir is not recommended. Raltegravir is a substrate of uridine diphosphate glucuronosyltransferase (UGT) 1A1; phenobarbital is a strong UGT1A1 inducer. Although not specifically studied with phenobarbital, other strong UGT1A1 inducers have been shown to decrease plasma concentrations of raltegravir, which may lead to HIV treatment failure or to the development of viral resistance.
    Calcium Carbonate: (Major) Coadministration of calcium carbonate with raltegravir administered as a once daily dose (high dose regimen) is not recommended. Coadministration may result in decreased plasma concentrations of raltegravir, which may lead to HIV treatment failure or the development of viral resistance. Calcium carbonate may be given with other dosage regimens of raltegravir with no dose adjustments necessary. In a drug interaction study (n = 19), the AUC of raltegravir, given as a single 1200 mg dose, was decreased by 72% (90% CI, 68% to 76%) when administered with a calcium carbonate antacid.
    Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Major) Coadministration of calcium carbonate with raltegravir administered as a once daily dose (high dose regimen) is not recommended. Coadministration may result in decreased plasma concentrations of raltegravir, which may lead to HIV treatment failure or the development of viral resistance. Calcium carbonate may be given with other dosage regimens of raltegravir with no dose adjustments necessary. In a drug interaction study (n = 19), the AUC of raltegravir, given as a single 1200 mg dose, was decreased by 72% (90% CI, 68% to 76%) when administered with a calcium carbonate antacid.
    Calcium Carbonate; Magnesium Hydroxide: (Major) Coadministration of calcium carbonate with raltegravir administered as a once daily dose (high dose regimen) is not recommended. Coadministration may result in decreased plasma concentrations of raltegravir, which may lead to HIV treatment failure or the development of viral resistance. Calcium carbonate may be given with other dosage regimens of raltegravir with no dose adjustments necessary. In a drug interaction study (n = 19), the AUC of raltegravir, given as a single 1200 mg dose, was decreased by 72% (90% CI, 68% to 76%) when administered with a calcium carbonate antacid.
    Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Major) Coadministration of calcium carbonate with raltegravir administered as a once daily dose (high dose regimen) is not recommended. Coadministration may result in decreased plasma concentrations of raltegravir, which may lead to HIV treatment failure or the development of viral resistance. Calcium carbonate may be given with other dosage regimens of raltegravir with no dose adjustments necessary. In a drug interaction study (n = 19), the AUC of raltegravir, given as a single 1200 mg dose, was decreased by 72% (90% CI, 68% to 76%) when administered with a calcium carbonate antacid.
    Calcium Carbonate; Risedronate: (Major) Coadministration of calcium carbonate with raltegravir administered as a once daily dose (high dose regimen) is not recommended. Coadministration may result in decreased plasma concentrations of raltegravir, which may lead to HIV treatment failure or the development of viral resistance. Calcium carbonate may be given with other dosage regimens of raltegravir with no dose adjustments necessary. In a drug interaction study (n = 19), the AUC of raltegravir, given as a single 1200 mg dose, was decreased by 72% (90% CI, 68% to 76%) when administered with a calcium carbonate antacid.
    Calcium Carbonate; Simethicone: (Major) Coadministration of calcium carbonate with raltegravir administered as a once daily dose (high dose regimen) is not recommended. Coadministration may result in decreased plasma concentrations of raltegravir, which may lead to HIV treatment failure or the development of viral resistance. Calcium carbonate may be given with other dosage regimens of raltegravir with no dose adjustments necessary. In a drug interaction study (n = 19), the AUC of raltegravir, given as a single 1200 mg dose, was decreased by 72% (90% CI, 68% to 76%) when administered with a calcium carbonate antacid.
    Calcium; Vitamin D: (Major) Coadministration of calcium carbonate with raltegravir administered as a once daily dose (high dose regimen) is not recommended. Coadministration may result in decreased plasma concentrations of raltegravir, which may lead to HIV treatment failure or the development of viral resistance. Calcium carbonate may be given with other dosage regimens of raltegravir with no dose adjustments necessary. In a drug interaction study (n = 19), the AUC of raltegravir, given as a single 1200 mg dose, was decreased by 72% (90% CI, 68% to 76%) when administered with a calcium carbonate antacid.
    Carbamazepine: (Major) Coadministration of carbamazepine with raltegravir is not recommended. Raltegravir is a substrate of uridine diphosphate glucuronosyltransferase (UGT) 1A1; carbamazepine is a strong UGT1A1 inducer. Although not specifically studied with carbamazepine, other strong UGT1A1 inducers have been shown to decrease plasma concentrations of raltegravir, which may lead to HIV treatment failure or to the development of viral resistance.
    Etravirine: (Major) Coadministration of etravirine with raltegravir administered as a once daily dose (high dose regimen) is not recommended. Raltegravir is a substrate of uridine diphosphate glucuronosyltransferase (UGT) 1A; etravirine is a UGT1A1 inducer. Coadministration may result in decreased raltegravir concentrations, although the effects of etravirine on the pharmacokinetics of raltegravir administered once daily have not been studied. Etravirine may be given with other dosage regimens of raltegravir with no dose adjustments necessary. In drug interaction studies, etravirine had no clinically meaningful effect on the pharmacokinetics of raltegravir 400 mg twice daily.
    Ezetimibe; Simvastatin: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
    Fenofibrate: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as fibric acid derivatives.
    Fenofibric Acid: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as fibric acid derivatives.
    Fibric acid derivatives: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as fibric acid derivatives.
    Fluvastatin: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
    Fosamprenavir: (Moderate) Coadministration of fosamprenavir with raltegravir may alter the serum concentrations of both medications. According to the manufacturer, the appropriate dose adjustments for coadministration have not been established. During clinical studies, ampenavir pharmacokinetic parameters were altered when various fosamprenavir doses (i.e., 700 mg BID, 1400 mg BID, 1400 mg daily) were administered concurrently with raltegravir 400 mg PO twice daily. The recorded amprenavir pharmacokinetic parameters ranged from a Cmax reduction of 27% to an increase of 27%, an AUC reduction of 36% to an increase of 13%, and a Cmin reduction of 17% to 50%.
    Fosphenytoin: (Major) Coadministration of fosphenytoin with raltegravir is not recommended. Raltegravir is a substrate of uridine diphosphate glucuronosyltransferase (UGT) 1A1; fosphenytoin is a strong UGT1A1 inducer. Although not specifically studied with fosphenytoin, other strong UGT1A1 inducers have been shown to decrease plasma concentrations of raltegravir, which may lead to HIV treatment failure or to the development of viral resistance.
    Gemfibrozil: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as fibric acid derivatives.
    HMG-CoA reductase inhibitors: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Coadministration of rifampin with raltegravir administered as a once daily dose (high dose regimen) is not recommended. Increase the raltegravir dose to 800 mg PO twice daily when administered as the twice daily regimen in adults. Concurrent use of raltegravir with rifampin has not been studied in pediatric patients. Raltegravir is a substrate of uridine diphosphate glucuronosyltransferase (UGT) 1A1; rifampin is a strong UGT1A1 inducer. Coadministration may result in decreased plasma raltegravir concentrations, which could lead to HIV treatment failure or to the development of viral resistance. In a drug interaction study, the AUC for raltegravir 400 mg was reduced by 40% when coadministered with rifampin. The effects of rifampin on the pharmacokinetics of raltegravir administered once daily are not known.
    Isoniazid, INH; Rifampin: (Major) Coadministration of rifampin with raltegravir administered as a once daily dose (high dose regimen) is not recommended. Increase the raltegravir dose to 800 mg PO twice daily when administered as the twice daily regimen in adults. Concurrent use of raltegravir with rifampin has not been studied in pediatric patients. Raltegravir is a substrate of uridine diphosphate glucuronosyltransferase (UGT) 1A1; rifampin is a strong UGT1A1 inducer. Coadministration may result in decreased plasma raltegravir concentrations, which could lead to HIV treatment failure or to the development of viral resistance. In a drug interaction study, the AUC for raltegravir 400 mg was reduced by 40% when coadministered with rifampin. The effects of rifampin on the pharmacokinetics of raltegravir administered once daily are not known.
    Lovastatin: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
    Lovastatin; Niacin: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
    Magnesium Hydroxide: (Major) Coadministration or staggered administration of aluminum and/or magnesium-containing antacids is not recommended during treatment with raltegravir. Coadministration may result in decreased plasma concentrations of raltegravir, which may lead to HIV treatment failure or the development of viral resistance. In a drug interaction study, the AUC for raltegravir was decreased by 49% (90% CI, 35% to 60%), 51% (90% CI, 33% to 65%), and 30% (90% CI, 4% to 50%), when administered with, 2 hours before, and 2 hours after aluminum/magnesium hydroxide antacids, respectively.
    Niacin; Simvastatin: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
    Phenobarbital: (Major) Coadministration of phenobarbital with raltegravir is not recommended. Raltegravir is a substrate of uridine diphosphate glucuronosyltransferase (UGT) 1A1; phenobarbital is a strong UGT1A1 inducer. Although not specifically studied with phenobarbital, other strong UGT1A1 inducers have been shown to decrease plasma concentrations of raltegravir, which may lead to HIV treatment failure or to the development of viral resistance.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Coadministration of phenobarbital with raltegravir is not recommended. Raltegravir is a substrate of uridine diphosphate glucuronosyltransferase (UGT) 1A1; phenobarbital is a strong UGT1A1 inducer. Although not specifically studied with phenobarbital, other strong UGT1A1 inducers have been shown to decrease plasma concentrations of raltegravir, which may lead to HIV treatment failure or to the development of viral resistance.
    Phenytoin: (Major) Coadministration of phenytoin with raltegravir is not recommended. Raltegravir is a substrate of uridine diphosphate glucuronosyltransferase (UGT) 1A1; phenytoin is a strong UGT1A1 inducer. Although not specifically studied with phenytoin, other strong UGT1A1 inducers have been shown to decrease plasma concentrations of raltegravir, which may lead to HIV treatment failure or to the development of viral resistance.
    Pitavastatin: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
    Pravastatin: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
    Primidone: (Major) Coadministration of primidone with raltegravir is not recommended. Raltegravir is a substrate of uridine diphosphate glucuronosyltransferase (UGT) 1A1; phenobarbital, the active metabolite of primidone, is a strong UGT1A1 inducer. Although not specifically studied with phenobarbital, other strong UGT1A1 inducers have been shown to decrease plasma concentrations of raltegravir, which may lead to HIV treatment failure or to the development of viral resistance.
    Rifampin: (Major) Coadministration of rifampin with raltegravir administered as a once daily dose (high dose regimen) is not recommended. Increase the raltegravir dose to 800 mg PO twice daily when administered as the twice daily regimen in adults. Concurrent use of raltegravir with rifampin has not been studied in pediatric patients. Raltegravir is a substrate of uridine diphosphate glucuronosyltransferase (UGT) 1A1; rifampin is a strong UGT1A1 inducer. Coadministration may result in decreased plasma raltegravir concentrations, which could lead to HIV treatment failure or to the development of viral resistance. In a drug interaction study, the AUC for raltegravir 400 mg was reduced by 40% when coadministered with rifampin. The effects of rifampin on the pharmacokinetics of raltegravir administered once daily are not known.
    Rosuvastatin: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
    Rosuvastatin; Ezetimibe: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
    Simvastatin: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
    Simvastatin; Sitagliptin: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
    Tipranavir: (Major) Coadministration of tipranavir plus ritonavir with raltegravir administered as a once daily dose (high dose regimen) is not recommended, as concurrent use results in decreased raltegravir concentrations. Tipranavir/ritonavir may be given with other dosage regimens of raltegravir with no dose adjustments necessary. Raltegravir is a substrate of uridine diphosphate glucuronosyltransferase (UGT) 1A1; tipranavir given with ritonavir is a UGT1A1 inducer. In drug interaction studies, tipranavir; ritonavir had no clinically meaningful effect on the pharmacokinetics of raltegravir 400 mg twice daily.

    PREGNANCY AND LACTATION

    Pregnancy

    Antiretroviral therapy should be provided to all women during pregnancy, regardless of HIV RNA concentrations or CD4 cell count. Using highly active antiretroviral combination therapy (HAART) to maximally suppress viral replication is the most effective strategy to prevent the development of resistance and to minimize the risk of perinatal transmission. In treatment-naive women, begin HAART as soon as pregnancy is recognized or HIV is diagnosed, without waiting for the results of resistance testing; subsequent modifications to the treatment regimen should be made once the test results are available. Women who are currently receiving antiretroviral treatment when pregnancy is recognized should continue their treatment regimen if it is currently effective in suppressing viral replication; consider resistance testing if HIV RNA concentrations are more than 500 copies/mL. For women not currently receiving HAART, but who have previously received treatment, obtain a complete and accurate history of all prior antiretroviral regimens used and results of prior resistance testing, and perform resistance testing if HIV RNA concentrations are more than 500 copies/mL; treatment should be initiated prior to receiving resistance test results. HIV guidelines recommend raltegravir, administered via twice-daily dosing, as a preferred treatment option for use in pregnant women. In addition, because of its ability to rapidly suppress viral load (approximately 2-log copies/mL decrease after 2 weeks of treatment), raltegravir may be a preferred option for use late in pregnancy in women with high viral loads. For non-pregnant women who are trying to conceive, raltegravir may be considered as a preferred option as no cases of neural tube defects (a birth defect associated with use of another integrase inhibitor) have been reported following use of raltegravir around the time of conception. Available data from the Antiretroviral Pregnancy Registry (APR), which includes over 480 first trimester exposures to raltegravir, have shown no difference in the risk of overall major birth defects when compared to the 2.7% background rate among pregnant women in the US. The prevalence of birth defects was 3.1% (95% CI: 1.7% to 5%) when exposure occurred in the first trimester. Supplemental data from the APR regarding central nervous system birth defects are available. Among the reported exposures to raltegravir (327 periconception, 95 late first trimester, 399 second/third trimester), 1 central nervous system birth defect was identified during the last first trimester; however, this was not a neural tube or encephalocele defect. Regular laboratory monitoring is recommended to determine antiretroviral efficacy. Monitor CD4 counts at the initial visit. Women who have been on HAART for at least 2 years and have consistent viral suppression and CD4 counts consistently greater than 300 cells/mm3 do not need CD4 counts monitored after the initial visit during the pregnancy. However, CD4 counts should be monitored every 3 months during pregnancy for women on HAART less than 2 years, women with CD4 count less than 300 cells/mm3, or women with inconsistent adherence or detectable viral loads. Monitor plasma HIV RNA at the initial visit, 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, then at least every 3 months during pregnancy, and at 34 to 36 weeks gestation. Perform antiretroviral resistance assay (genotypic testing, and if indicated, phenotypic testing) at baseline in all women with HIV RNA concentrations more than 500 copies/mL, unless they have already been tested for resistance. First trimester ultrasound is recommended to confirm gestational age and provide an accurate estimation of gestational age at delivery. A second trimester ultrasound can be used for both anatomical survey and determination of gestational age in those patients not seen until later in gestation. Perform standard glucose screening in women receiving antiretroviral therapy at 24 to 28 weeks gestation, although it should be noted that some experts would perform earlier screening with ongoing chronic protease inhibitor-based therapy initiated prior to pregnancy, similar to recommendations for women with high-risk factors for glucose intolerance. Liver function testing is recommended within 2 to 4 weeks after initiating or changing antiretroviral therapy, and approximately every 3 months thereafter during pregnancy (or as needed). All pregnant women should be counseled about the importance of adherence to their antiretroviral regimen to reduce the potential for development of resistance and perinatal transmission. It is strongly recommended that antiretroviral therapy, once initiated, not be discontinued. If a woman decides to discontinue therapy, a consultation with an HIV specialist is recommended. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to raltegravir; information about the registry can be obtained at www.apregistry.com or by calling 1-800-258-4263.[27468] [23512] [33530] [46638]

    To reduce the risk of postnatal transmission, mothers with HIV within the United States are advised by the Centers for Disease Control and Prevention to avoid breast-feeding. This recommendation applies to both untreated women and women who are receiving antiretroviral therapy, including raltegravir. If a mother with HIV opts to breast-feed, the infant should undergo immediate diagnostic and virologic HIV testing. Testing should continue throughout breast-feeding and up to 6 months after cessation of breast-feeding. For expert consultation, health care workers may contact the Perinatal HIV Hotline (888-448-8765).[42452] There are no data on the presence of raltegravir in human milk, the effects on the breastfed infant, or the effects on the milk production. Antiretroviral medications whose passage into human breast milk have been evaluated include nevirapine, zidovudine, lamivudine, and nelfinavir.

    MECHANISM OF ACTION

    Raltegravir inhibits the catalytic activity of HIV integrase, which is an HIV encoded enzyme required for viral replication. Integrase is 1 of the 3 HIV-1 enzymes required for viral replication. Integration of HIV into cellular DNA is a multi-step process. First, the assembly of integrase in a stable complex with the viral DNA occurs. Second, the terminal dinucleotide from each 39 end of the viral DNA is removed by endonucleolytic processing. Lastly, the viral DNA 3' ends are covalently linked to the cellular (target) DNA by strand transfer. The last 2 processes, which are catalytic, require integrase to be appropriately assembled on a specific viral DNA substrate. Inhibition of integrase by raltegravir prevents the covalent insertion, or integration, of unintegrated linear HIV DNA into the host cell genome preventing the formation of the HIV provirus. The provirus is required to direct the production of progeny virus, so inhibiting integration prevents propagation of the viral infection. Raltegravir did not significantly inhibit human phosphoryl transferases including DNA polymerases alpha, beta, and gamma.
     
    No dose-response effect occurred over the dose range of 200 to 600 mg orally twice daily. After 24 weeks of raltegravir plus optimized background therapy, the mean viral load reduction from baseline was 1.8 log10 copies/mL for raltegravir 200 mg twice daily, 1.87 log10 copies/mL for 400 mg twice daily, and 1.84 log10 copies/ml for 600 mg twice daily. A similar percentage of patients had a HIV-1 RNA of less than 400 copies/mL: 69.8% of the 200 mg group, 71.1% of the 400 mg group, and 71.1% of the 600 mg group. Of note, 72% of the study population's viral isolate was not sensitive to any antiretroviral in their optimized background regimen.
     
    Twice daily administration led to a mean concentration of 70.6 nM 12 hours after a 100 mg dose. The geometric mean concentration was 107.1 nM after dosing with 200 mg and 200.6 nM after dosing with 400 mg. Raltegravir at concentrations of 31 +/- 20 nM resulted in 95% inhibition (EC95) of viral spread relative to an untreated virus-infected culture in human T-lymphoid cell cultures infected with the cell-line adapted HIV-1 variant H9IIIB. In addition, concentrations of 6 to 50 nM resulted in 95% inhibition of viral spread in cultures of mitogen-activated human peripheral blood mononuclear cells infected with diverse, primary clinical isolates of HIV-1, including isolates resistant to reverse transcriptase inhibitors and protease inhibitors. Raltegravir also inhibited replication of an HIV-2 isolate when tested in CEMx174 cells (EC95 of 6 nM). Additive to synergistic antiretroviral activity was observed when human T-lymphoid cells infected with the H9IIIB variant of HIV-1 were incubated with raltegravir and delavirdine, efavirenz, nevirapine, abacavir, didanosine, lamivudine, stavudine, tenofovir, zalcitabine, zidovudine, amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or enfuvirtide.
     
    Among 160 treatment-naive patients who got raltegravir, lamivudine, and tenofovir for 48 weeks, 5 had virologic failure. The N155H amino acid substitution in the integrase region was noted in 2 patients; the substitution was not present before treatment. Two other patients had resistance-conferring mutations detected in the reverse transcriptase region only. The last patient had virus with no known resistance mutations. Mutations observed in the HIV-1 integrase coding sequence that contributed to raltegravir resistance generally included an amino acid substitution at either Y143, Q148, or N155 plus one or more additional substitutions.
     
    Cross-resistance with other HIV-1 integrase strand transfer inhibitors (ISTIs) has been identified; generally, mutations conferring resistance to raltegravir also confer resistance to elvitegravir. Specific amino acid substitutions resulting in reduced susceptibility to the ISTI class include Y143, E92Q, and Q148 plus.

    PHARMACOKINETICS

    Raltegravir is administered orally. It is approximately 83% bound to human plasma protein over the concentration range of 2 to 10 micromole. It distributes into the cerebrospinal fluid (CSF) at a proportion 3-fold lower than the free fraction in plasma, with median CSF concentration being 5.8% (range: 1% to 53.5%) of the corresponding plasma concentration. Elimination is mainly by metabolism via a UDP-glucuronosyltransferases 1A1 (UGT1A1)-mediated glucuronidation pathway. Data are not sufficient to determine the impact of UGT1A1 polymorphism on pharmacokinetic parameter values. The apparent terminal half-life is approximately 9 hours. Approximately 51% of an oral, radiolabeled dose was excreted in the feces, and 32% was excreted in urine. In feces, only raltegravir was present. Most of the drug in the feces is likely derived from hydrolysis of raltegravir-glucuronide secreted in bile. In urine, both raltegravir (9%) and raltegravir-glucuronide (23%) were detected. The major circulating entity was raltegravir and represented approximately 70% of the total radioactivity; the remaining radioactivity in plasma was accounted for by raltegravir-glucuronide.
     
    Affected cytochrome P450 isoenzymes: none
    In vitro, raltegravir does not induce cytochrome P450 (CYP) 3A4, CYP1A2, or CYP2B6, nor does it inhibit UGT1A1, UGT2B7, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A. It does not inhibit P-glycoprotein (P-gp)-mediated transport. Raltegravir is not a substrate of CYP enzymes.

    Oral Route

    The absolute bioavailability of raltegravir is unknown. Based on a formulation comparison study in healthy adults, the oral suspension has a higher bioavailability than the chewable tablets, and both have a higher bioavailability than the 400 mg film-coated tablet. Relative to the 400 mg film-coated tablet, the 600 mg film-coated tablet has a higher bioavailability. The AUC and Cmax increase proportionally over the dosage range of 100 to 1,600 mg. The concentration 12 hours after administration increases slightly less than proportionally over the dosage range of 100 to 1,600 mg. Steady state is achieved within approximately the first 2 days of dosing. Little to no accumulation in AUC and Cmax occurs for the 400 mg twice daily and 1,200 mg once daily formulations.
     
    Effects of Food
    Raltegravir may be taken with or without food; it was administered without regard to food in the pivotal safety and efficacy studies. The time to maximum absorption in the fasted state is approximately 3 hours for the 400 mg film-coated tablet and 1.5 to 2 hours for the 600 mg film-coated tablet. When the 400 mg film-coated tablet was administered with a high-fat meal, the systemic exposure (AUC) and Cmax were increased by about 2-fold. Administration with a moderate-fat meal did not affect the AUC to a clinically meaningful degree. Administration with a low-fat meal decreased the AUC by 46% and the Cmax by 52%. When the 600 mg film-coated tablet was administered with a high-fat meal, the AUC was not affected to a clinically meaningful degree. The Cmax was decreased by 28%. Administration with a low-fat meal decreased the AUC by 42% and the Cmax by 52%. When the chewable tablet was administered with a high fat-meal, the AUC was not affected to a clinically meaningful degree. The Cmax was decreased by 62%. The effects of food on the pharmacokinetic parameters of the oral suspension have not been studied.