AHFS Class:

• HIV Integrase Inhibitors 8:18.08.12

Generic Name(s):

• Raltegravir Potassium

Raltegravir potassium, an antiretroviral agent, is a human immunodeficiency virus (HIV) integrase strand transfer inhibitor (INSTI).1,200

Treatment of HIV Infection

Raltegravir is used in conjunction with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients weighing ≥2 kg (Isentress^®) or pediatric patients weighing ≥40 kg (Isentress^® HD).1,2,14,15,17,18,24,25,26,27

Raltegravir is commonly used as part of a fully suppressive antiretroviral regimen; consult guidelines for the most current information on recommended regimens.200,201,202 Selection of an initial antiretroviral regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance test results, comorbid conditions, access, and cost.200,201,202

Clinical Experience

Antiretroviral-naïve Adults

The comparative efficacy of raltegravir (twice daily) and efavirenz (once daily) for the treatment of HIV-1 infection in antiretroviral-naïve adults was evaluated in a phase 3, randomized, active-control study (STARTMRK).1,17 The comparative efficacy of raltegravir (twice daily) and raltegravir (once daily) in antiretroviral-naïve, HIV-infected adults was evaluated in a phase 3, randomized, double-blind, parallel-group, noninferiority study (ONCEMRK).1,24

In STARTMRK, 563 antiretroviral-naïve adults with baseline plasma HIV-1 RNA levels >5000 copies/mL were randomized to receive raltegravir (400-mg tablet twice daily) or efavirenz (600 mg once daily) in conjunction with the fixed combination of emtricitabine and tenofovir disoproxil fumarate (emtricitabine/tenofovir DF).1,17 At baseline, enrolled patients had a median age of 37 years (range: 19-71 years), 81% were male, 58% were non-white, 53% had baseline plasma HIV-1 RNA levels exceeding 100,000 copies/mL, 47% had baseline CD4+ T-cell counts <200 cells/mm³, and 6% had hepatitis B virus (HBV) or hepatitis C virus (HCV) coinfection.1 At 240 weeks, 66% of those receiving the twice-daily raltegravir regimen had plasma HIV-1 RNA levels <50 copies/mL compared with 60% of those receiving once-daily efavirenz.1,17

In ONCEMRK, 797 antiretroviral-naïve adults with baseline plasma HIV-1 RNA levels of ≥1000 copies/mL were randomized to receive 1.2 g of raltegravir once daily (two 600-mg tablets once daily) or 400 mg of raltegravir twice daily (400-mg tablet twice daily) in conjunction with the fixed combination emtricitabine/tenofovir DF.1,24 At baseline, enrolled patients had a median age of 34 years (range: 18-84 years), 85% were male, 41% were non-white, 28% had baseline plasma HIV-1 RNA levels exceeding 100,000 copies/mL, 13% had baseline CD4+ T-cell counts <200 cells/mm³, and 3% had HBV and/or HCV coinfection.1 At 96 weeks, 82% of the patients randomized to the once-daily raltegravir regimen (433/531 patients) and 80% of those randomized to the twice-daily raltegravir regimen (213/266 patients) had plasma HIV-1 RNA levels <40 copies/mL and the mean change in CD4+ T-cell count from baseline was 262 cells/mm³ in both treatment groups.1,24 These results indicate that the once-daily raltegravir regimen is noninferior to the twice-daily raltegravir regimen in antiretroviral-naïve adults.1,24

Efficacy of a 2-drug antiretroviral regimen of ritonavir-boosted darunavir and raltegravir for the treatment of HIV-1 infection in antiretroviral-naïve adults was evaluated in a randomized, open-label, noninferiority trial (NEAT/ANRS 143).25 In this study, 805 antiretroviral-naïve adults with plasma HIV-1 RNA levels >1000 copies/mL were randomized 1:1 to receive a 2-drug regimen of ritonavir-boosted darunavir (800 mg of darunavir and 100 mg of ritonavir once daily) in conjunction with raltegravir (400 mg twice daily) or a 3-drug regimen of ritonavir-boosted darunavir (800 mg of darunavir and 100 mg of ritonavir once daily) in conjunction with the fixed combination emtricitabine/tenofovir DF.25 Baseline characteristics were similar in both treatment groups.25 At 96 weeks, the 2-drug regimen was noninferior to the 3-drug regimen based on the primary end point of proportion of patients with virologic or clinical failure (19% patients receiving the 2-drug regimen and 15% of those receiving the 3-drug regimen experienced treatment failure).25 However, among those with baseline CD4+ T-cell counts <200 cells/mm³, there were more virologic failures in the 2-drug arm than in the 3-drug arm and a trend towards more virologic failures was observed among those with baseline plasma HIV-1 RNA levels of ≥100,000 copies/mL.25 In a smaller open-label, randomized study in antiretroviral-naïve adults, a 2-drug regimen of ritonavir-boosted darunavir and raltegravir was associated with high rates of virologic failure in the subgroup of patients with baseline plasma HIV-1 RNA levels exceeding 100,000 copies/mL.26

Raltegravir (400 mg twice daily) was compared to efavirenz (600 mg nightly), both in combination with lamivudine (150 mg twice daily) and zidovudine (300 mg twice daily) or an alternate nucleoside reverse transcriptase inhibitor (NRTI) backbone, in pregnant women living with HIV in a randomized, multicenter, open-label, Phase 4 trial (NICHD P1081).27 Participants were antiretroviral-naïve with gestational age between 20 and 36 weeks.27 The primary efficacy outcome was maternal virologic response, defined as a plasma HIV-1 viral load <200 copies/mL, within 21 days prior to delivery. Among 408 patients who were randomized, median age was 27 years and median gestational age was 27 weeks; most patients were Hispanic (52%) or non-Hispanic Black (36%).27 In the primary analysis, patients receiving raltegravir-based therapy experienced a significantly higher rate of virologic suppression at delivery than those receiving efavirenz-based therapy (94 and 84%, respectively).27 Subgroup analysis indicated differences in response rate were associated with gestational age at study entry.27 In patients who entered the study at a gestational age between 20 and 27 weeks, rates of virologic suppression at delivery were similar between treatment arms.27 However, in patients who entered the study at a gestational age between 28 and 36 weeks, those assigned to raltegravir-based treatment achieved substantially greater virologic suppression at delivery compared to patients assigned to efavirenz-based treatment.27

Antiretroviral-experienced Adults

Raltegravir has been evaluated in 2 phase 3, randomized, double-blind, placebo-controlled, multicenter studies (BENCHMRK 1, BENCHMRK 2) in antiretroviral-experienced adults with documented resistance to at least one HIV NRTI, HIV nonnucleoside reverse transcriptase inhibitor (NNRTI), and HIV protease inhibitor (PI).1,2 14,18 Patients enrolled in these studies were adults 16 years of age or older (mean age 45 years, 88-89% male, 65-73% white, 11-14% Black, 3% Asian, 8-11% Hispanic, median baseline plasma HIV-1 RNA level 4.7-4.8 log₁₀ copies/mL, median baseline CD4+ T-cell count 119-123 cells/mm³) who had previously received various antiretrovirals (median number of previous antiretrovirals was 12) for a median duration of 10 years.1 All patients received an optimized background antiretroviral regimen (OBR; selected on the basis of the individual's prior antiretroviral treatment and results of genotypic/phenotypic viral resistance testing; median number of antiretrovirals in the OBR was 4).1,2 14,18 A total of 699 patients were randomized to receive raltegravir 400 mg twice daily or placebo in conjunction with an OBR.1 14,18 Random assignment was stratified by degree of resistance to PIs at study entry (i.e., resistant to one PI or more than one PI [95-97% were resistant to more than one PI]) and use of enfuvirtide in the OBR (38% received enfuvirtide).1 18 At 96 weeks, pooled analysis of these 699 patients indicated that 55% of those randomized to raltegravir in conjunction with an OBR had plasma HIV-1 RNA levels <50 copies/mL compared with 27% of those randomized to placebo and an OBR; the mean increase in CD4+ T-cell count was 118 and 47 cells/mm³, respectively.1 At 156 weeks (after completion of the double-blind treatment period), 251 patients from the raltegravir group and 47 patients from the placebo group received open-label treatment with raltegravir (400 mg twice daily) in conjunction with an OBR.18 At 240 weeks (after 84 weeks of open-label treatment), 77% of patients originally enrolled in the raltegravir group had plasma HIV-1 RNA levels <50 copies/mL compared with 81% of patients originally enrolled in the placebo group; the mean increase in CD4+ T-cell count from baseline was 293 and 267 cells/mm³, respectively. 18

Two phase 3 studies designed to evaluate the use of raltegravir and 2 NRTIs in patients who had been receiving a suppressive regimen of the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) and 2 NRTIs were terminated early based on 24-week data that failed to demonstrate non-inferiority of switching to raltegravir versus continuing the lopinavir/ritonavir regimen (SWITCHMRK 1 and 2).1 In these studies, a total of 352 HIV- 1-infected patients who had been receiving a regimen of lopinavir/ritonavir and at least 2 NRTIs for longer than 3 months and had plasma HIV-1 RNA levels <50 copies/mL were randomized to either continue the lopinavir/ritonavir regimen or be switched to raltegravir (400 mg twice daily) with the NRTIs.1 At 24 weeks, combined analysis of the studies indicated that plasma HIV-1 RNA levels <50 copies/mL were maintained in 90% of those who continued the lopinavir/ritonavir regimen compared with 82% of those who were switched to the raltegravir regimen.1

Pediatric Patients

Efficacy of raltegravir in conjunction with other antiretrovirals in pediatric patients have been evaluated in a phase 1/phase 2 open-label study (IMPAACT P1066) that included 126 antiretroviral-experienced HIV-infected children and adolescents 2-18 years of age.1 These pediatric patients were enrolled into the following cohorts based on age and received raltegravir in conjunction with an OBR: cohort I (12 to <18 years of a 400 mg film-coated tablets), cohort IIa (6 to <12 years of a 400 mg film-coated tablets), cohort IIb (6 to <12 years old; chewable tablets), and cohort III (2 to <6 years of a chewable tablets).1 In the initial dose-finding stage, raltegravir dosage was selected to achieve raltegravir plasma exposures and trough concentrations similar to those reported in adults and acceptable short-term safety.1 After dose selection, additional patients were enrolled for evaluation of long-term safety, tolerability, and efficacy.1 Of the initial 126 patients in cohorts I, IIa, IIb, and III, 96 received the recommended dosage of raltegravir (median age 13 years, 51% female, 34% white, 59% Black, mean baseline plasma HIV-1 RNA level 4.3 log₁₀ copies/mL, median baseline CD4+ T-cell count 481 cells/mm³, median CD4 percentage 23%).1 A total of 93 of these patients completed 24 weeks of treatment and 91 completed 48 weeks of treatment.1,15 At week 24, 66 and 54% had achieved plasma HIV-1 RNA levels <400 and 50 copies/mL, respectively; the mean increase in CD4+ T-cell count from baseline was 119 cells/mm³, and the mean increase in CD4+ T-cell percentage from baseline was 3.8%.15 At week 48, 74 and 57% had achieved plasma HIV-1 RNA levels <400 and 50 copies/mL, respectively; the mean increase in CD4+ T-cell count from baseline was 156 cells/mm³, and the mean increase in CD4+ T-cell percentage from baseline was 4.6%.15

IMPAACT P1066 also evaluated the safety and efficacy of raltegravir oral suspension in conjunction with an OBR in children 4 weeks to <2 years of age (cohorts IV and V).1 The 26 patients enrolled in cohorts IV and V (median age 28 weeks, 35% female, 8% white, 85% Black, mean baseline plasma HIV-1 RNA level 5.7 log₁₀ copies/mL, median baseline CD4+ T-cell count 1400 cells/mm³, median CD4 percentage 18.6%) had previously received antiretroviral therapy as prophylaxis for prevention of perinatal HIV transmission and/or as combination antiretroviral therapy for treatment of HIV infection.1 Twenty-three patients were included in the 24-week and 48-week efficacy analyses.1 At week 24, 61 and 39% had achieved plasma HIV-1 RNA levels <400 and 50 copies/mL, respectively; the mean increase in CD4+ T-cell count from baseline was 500 cells/mm³, and the mean increase in CD4+ T-cell percentage from baseline was 7.5%.1 At week 48, 61 and 44% had achieved plasma HIV-1 RNA levels <400 and 50 copies/mL, respectively; the mean increase in CD4+ T-cell count from baseline was 492 cells/mm³, and the mean increase in CD4+ T-cell percentage from baseline was 7.8%.1

Clinical Perspective

Therapeutic options for the treatment and prevention of HIV infection and recommendations concerning the use of antiretrovirals are continuously evolving.200,201,202 Antiretroviral therapy (ART) is recommended for all individuals with HIV regardless of CD4 counts, and should be initiated as soon as possible after diagnosis of HIV and continued indefinitely.200,201,202 The primary goals of ART are to achieve and maintain durable suppression of HIV viral load (as measured by plasma HIV-1 RNA levels) to a level below which drug-resistance mutations cannot emerge (i.e., below detectable limits), restore and preserve immunologic function, reduce HIV-related morbidity and mortality, improve quality of life, and prevent transmission of HIV.200,202 While the most appropriate antiretroviral regimen cannot be defined for each clinical scenario, the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents, HHS Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV, and HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission, have developed comprehensive guidelines that provide information on selection and use of antiretrovirals for the treatment or prevention of HIV infection.200,201,202 Because of the complexity of managing patients with HIV, it is recommended that clinicians with HIV expertise be consulted when needed.200,201,202

The use of combination antiretroviral regimens that generally include 3 drugs from 2 or more drug classes is currently recommended to achieve viral suppression.200,201 In both treatment-naïve adults and children, an initial antiretroviral regimen generally consists of 2 NRTIs administered in combination with a third active antiretroviral drug from 1 of 3 drug classes: an INSTI, a NNRTI, or a PI with a pharmacokinetic enhancer (also known as a booster; the 2 drugs used for this purpose are cobicistat and ritonavir).200,201,202 Selection of an initial antiretroviral regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance-test results, comorbid conditions, access, and cost.200,201,202 In patients with comorbid infections (e.g., hepatitis B, tuberculosis), regimen selection should also consider the potential for activity against other present infections and timing of initiation relative to other anti-infective regimens.200

In the 2023 HHS adult and adolescent HIV treatment guideline, raltegravir, an INSTI, is included in various antiretroviral regimens.200 Some of these raltegravir-containing regimens are listed among recommended or alternative initial regimens in certain clinical situations, and include the following regimens: raltegravir plus tenofovir alafenamide or tenofovir DF plus emtricitabine or lamivudine, or, when abacavir, tenofovir alafenamide, and tenofovir DF cannot be used or are not optimal, ritonavir-boosted darunavir plus raltegravir twice a day ( only in patients with CD4 count >200 cells/mm³ and HIV viral load <100,000 copies/mL).200

In the 2023 HHS pediatric HIV treatment guideline, raltegravir is included in various regimens.201 Raltegravir plus 2 NRTIs is a preferred initial regimen from birth to <4 weeks of age ( only in patients weighing ≥2 kg) and is recommended as an alternative initial regimen in patients ≥4 weeks of age ( only in patients weighing ≥2 kg).201

In the 2023 HHS perinatal HIV treatment guideline, raltegravir is included in various antiretroviral regimens.202 Raltegravir plus a preferred dual-NRTI backbone is listed as an alternative initial option for pregnant patients.202

Postexposure Prophylaxis following Occupational Exposure to HIV

Raltegravir is used in conjunction with 2 NRTIs for postexposure prophylaxis of HIV infection following occupational exposure (PEP)† in health-care personnel and other individuals exposed via percutaneous injury (e.g., needlestick, cut with sharp object) or mucous membrane or nonintact skin (e.g., chapped, abraded, dermatitis) contact with blood, tissue, or other body fluids that might contain HIV.199

The US Public Health Service (USPHS) states that the preferred regimen for PEP following an occupational exposure to HIV is a 3-drug regimen of raltegravir used in conjunction with emtricitabine and tenofovir DF (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada^®).199 These experts recommend several alternative regimens that include an INSTI (such as raltegravir), NNRTI, or PI and 2 NRTIs (dual NRTIs).199 The preferred dual NRTI option for use in PEP regimens is emtricitabine and tenofovir DF (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada^®); alternative dual NRTIs are tenofovir DF and lamivudine, lamivudine and zidovudine (may be administered as the fixed combination lamivudine/zidovudine; Combivir^®), or zidovudine and emtricitabine.199

Because management of occupational exposures to HIV is complex and evolving, consultation with an infectious diseases specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended whenever possible.199 However, initiation of PEP should not be delayed while waiting for expert consultation.199

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

Raltegravir is used in conjunction with other antiretrovirals for postexposure prophylaxis of HIV infection following nonoccupational exposure (nPEP)† in individuals exposed to blood, genital secretions, or other potentially infectious body fluids that might contain HIV when the exposure represents a substantial risk for HIV transmission.28,29,198 Raltegravir in combination with emtricitabine and tenofovir DF is a preferred regimen in guidelines for nPEP, and several raltegravir-containing combinations are listed as alternative regimens.198

Clinical Experience

Raltegravir in combination with tenofovir DF and emtricitabine has been evaluated as nPEP† in 2 non-comparative clinical trials.28,29 In the first study, 86 HIV-negative men who have sex with men received raltegravir in combination with tenofovir DF and emtricitabine for 28 days following potential sexual exposure to HIV.28 In the second study, 100 HIV-negative adults received raltegravir in combination with tenofovir DF and emtricitabine for 28 days following potential sexual exposure to HIV.29 Regimen completion rates were 92% and 57%, respectively; no patients in either study had developed HIV infection at 3-month follow-up.28,29

Clinical Perspective

When nPEP is indicated following a nonoccupational exposure to HIV, the US Centers for Disease Control and Prevention (CDC) states that the preferred regimen in adults and adolescents 13 years of age or older with normal renal function is either raltegravir or dolutegravir used in conjunction with emtricitabine and tenofovir DF (administered as the fixed combination emtricitabine/tenofovir DF; Truvada^®).198 The alternative nPEP regimen recommended in these patients is ritonavir-boosted darunavir used in conjunction with emtricitabine/tenofovir DF (Truvada^®).198 Raltegravir in combination with 2 other NRTIs is one of several other alterative regimens recommended by CDC for nPEP.198

Consultation with an infectious diseases specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended if nPEP is indicated in certain exposed individuals (e.g., pregnant women, children, those with medical conditions such as renal impairment) or if an antiretroviral regimen not included in the CDC guidelines is being considered, the source virus is known or likely to be resistant to antiretrovirals, or the healthcare provider is inexperienced in prescribing antiretrovirals.198 However, initiation of nPEP should not be delayed while waiting for expert consultation.198

General

Pretreatment Screening

• Evaluate patients for history of phenylketonuria.1
• Evaluate patients for history of rhabdomyolysis, myopathy, or increased creatine kinase.1
• Evaluate use of concomitant medications including statins, fenofibrate, gemfibrozil, or zidovudine.1

Patient Monitoring

• Monitor for symptoms of infection.1
• Monitor for rash associated with severe symptoms such as fever, extreme fatigue, hypersensitivity, and hepatotoxicity.1

Administration

Raltegravir potassium is available for oral administration as 400-mg and 600-mg (Isentress^® HD) film-coated tablets, 25-mg and 100-mg chewable tablets, and a 100-mg powder for oral suspension.1 Raltegravir is administered orally once or twice daily without regard to food.1 Use the drug in conjunction with other antiretrovirals.

Chewable Tablets

Raltegravir chewable tablets may be chewed or swallowed whole.1 If necessary, the 100-mg chewable tablet can be divided into equal halves.1 For children who have difficulty chewing, the 25 mg chewable tablet can be crushed.1 To administer, place the chewable tablet in a small, clean cup and add a teaspoonful (5 mL) of a liquid such as water, juice, or breast milk.1 Within 2 minutes, the tablet(s) will absorb the liquid and fall apart.1 Crush any remaining pieces with a spoon and immediately administer the entire dose orally.1 For any remaining portion of the dose, add another teaspoonful of liquid, swirl, and administer immediately.1

The chewable tablets are used in pediatric patients 4 weeks of age or older weighing at least 3 kg to less than 25 kg.1 If necessary, the chewable tablets may be used as an alternative in pediatric patients weighing 25 kg or more who are not able to swallow the film-coated tablets; however, the film-coated tablets are the preferred formulation in pediatric patients weighing 25 kg or more if they can swallow a tablet.1

Store raltegravir chewable tablets at 20-25°C (excursions permitted between 15-30°C).1 Keep bottle tightly closed; do not remove desiccant.1

Film-coated Tablets

Raltegravir film-coated tablets must be swallowed whole.1 Raltegravir (Isentress^®) 400-mg film-coated tablets are used in adults and pediatric patients weighing 25 kg or more.1 Raltegravir (Isentress^® HD) 600-mg film-coated tablets are used in adults and pediatric patients weighing 40 kg or more.1

Store raltegravir film-coated tablets at 20-25°C (excursions permitted between 15-30°C).1 Keep bottle tightly closed; do not remove desiccant.1

Powder for Oral Suspension

Raltegravir powder for oral suspension is provided in single-use packets containing 100 mg of raltegravir and is used in pediatric patients weighing 2 kg to less than 20 kg.1 When the oral suspension is used, the maximum dosage is 100 mg twice daily.1 To prepare the oral suspension, use the proper syringe provided by the manufacturer to measure and add 10 mL of water to the mixing cup provided by the manufacturer.1 Add the entire contents of a single-use packet of raltegravir for oral suspension to the water in the mixing cup and tightly close the mixing cup and gently swirl in a circular motion for 45 seconds.1 If the powder is not completely mixed, gently swirl the mixing cup some more.1 Do not shake the mixing cup; the oral suspension will appear cloudy.1 Withdraw the recommended dosage of the oral suspension into the correct dosing syringe provided by the manufacturer and administer orally.1 After each use, handwash the dosing syringe and mixing cup with warm water and dish soap, rinse with water, and air dry.1

Do not open the foil packets containing the powder for oral suspension until ready to use.1 After the contents of the packet are suspended in water, use the oral suspension within 30 minutes and discard any unused portion.1

Store raltegravir powder for oral suspension at 20-25°C (excursions permitted between 15-30°C).1

Dosage

Raltegravir chewable tablets, film-coated tablets, and powder for oral suspension contain raltegravir potassium; dosage is expressed in terms of raltegravir.1

Because the formulations have different pharmacokinetic profiles, raltegravir chewable tablets and oral suspension are not bioequivalent to raltegravir film-coated tablets.1 Do not substitute the chewable tablets or oral suspension for the 400- or 600-mg film-coated tablets.1

Adults

Treatment of HIV-1 Infection in Antiretroviral-naïve Adults

For the initial treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral-naïve adults, the recommended dosage of raltegravir is 400 mg twice daily (one 400-mg film-coated tablet twice daily).1 Alternatively, 1.2 g of raltegravir can be given once daily (two 600-mg film-coated tablets once daily).1

When raltegravir is used in antiretroviral-naÏve adults receiving rifampin, the drug should be given in a dosage of 800 mg twice daily (two 400-mg film-coated tablets twice daily).1

Treatment of HIV-1 Infection in Antiretroviral-experienced Adults

For the treatment of HIV-1 infection in antiretroviral-experienced adults, the recommended dosage of raltegravir is 400 mg twice daily (one 400-mg film-coated tablet twice daily).1 In adults who are virologically suppressed on an initial regimen of raltegravir 400 mg twice daily, the same twice-daily raltegravir regimen can be continued or the patient may be switched to a regimen of 1.2 g of raltegravir once daily (two 600-mg film-coated tablets once daily).1

When raltegravir is used in antiretroviral-experienced adults receiving rifampin, the drug should be given in a dosage of 800 mg twice daily (two 400-mg film-coated tablets twice daily).1

Postexposure Prophylaxis following Occupational Exposure to HIV

For postexposure prophylaxis of HIV infection following occupational exposure (PEP)† in health-care personnel or other individuals, the recommended dosage of raltegravir is 400 mg twice daily.199 Raltegravir usually is used in conjunction with emtricitabine and tenofovir disoproxil fumarate (DF).199 PEP should be initiated as soon as possible following occupational exposure to HIV (preferably within hours) and continued for 4 weeks, if tolerated.199

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

For postexposure prophylaxis of HIV infection following nonoccupational exposure (nPEP)† when the exposure represents a substantial risk for HIV transmission, the usual adult dosage of raltegravir is 400 mg twice daily in conjunction with 2 HIV nucleoside reverse transcriptase inhibitors (NRTIs).198

The nPEP regimen should be initiated as soon as possible (within 72 hours) following nonoccupational exposure to HIV and continued for 28 days.198 If the exposed individual seeks care more than 72 hours after the exposure, nPEP is not recommended.198

Pediatric Dosage

Treatment of HIV-1 Infection

When raltegravir is used for the treatment of HIV-1 infection in full-term neonates (birth through 4 weeks [28 days] of age) weighing at least 2 kg, the powder for oral suspension should be used and dosage is based on weight.1 A once-daily raltegravir regimen is recommended in neonates up to 1 week of age and a twice-daily regimen is recommended in those 1-4 weeks of age.1 (See Table 1.)

When raltegravir is used for the treatment of HIV-1 infection in pediatric patients 4 weeks of age or older weighing 3 to less than 20 kg, the powder for oral suspension or chewable tablets can be used.1 For patients weighing less than 14 kg, the chewable tablets can be crushed.1 The chewable tablets should be used in pediatric patients weighing 20 to less than 25 kg.1 Dosage is based on weight and depends on whether the powder for oral suspension or chewable tablets are used.1 A twice-daily raltegravir regimen is used in these pediatric patients.1 (See Table 2.)

For the treatment of HIV-1 infection in pediatric patients weighing 25 kg or more, raltegravir film-coated tablets are preferred, but the chewable tablets can be used in those unable to swallow the film-coated tablets.1 When the chewable tablets are used in pediatric patients weighing 25 kg or more, dosage is based on weight and a twice-daily raltegravir regimen is used.1 (See Table 3.)

For the treatment of HIV-1 infection in pediatric patients weighing 25 to less than 40 kg who can swallow the film-coated tablets, the recommended raltegravir dosage is 400 mg twice daily (one 400-mg film-coated tablet twice daily).1

For the treatment of HIV-1 infection in antiretroviral-naïve pediatric patients weighing 40 kg or more, the recommended dosage of raltegravir is 400 mg twice daily (one 400-mg film-coated tablet twice daily).1 Alternatively, antiretroviral-naïve pediatric patients weighing 40 kg or more can receive 1.2 g of raltegravir once daily (two 600-mg film-coated tablets once daily).1 For those who are virologically suppressed on an initial regimen of raltegravir 400 mg twice daily, the same twice-daily raltegravir regimen can be continued or the patient may be switched to a regimen of 1.2 g of raltegravir once daily (two 600-mg film-coated tablets once daily).1

Special Populations

Hepatic Impairment

Dosage adjustment of raltegravir (twice daily) is not needed in patients with mild to moderate hepatic impairment.1 Pharmacokinetics of raltegravir have not been studied in those with severe hepatic impairment.1

Raltegravir (once daily) has not been studied in patients with hepatic impairment and is not recommended in patients with hepatic impairment.1

Renal Impairment

Dosage adjustment of raltegravir (once or twice daily) is not needed in patients with renal impairment.1

Because the extent to which raltegravir is removed by dialysis is not known, administering the drug before a dialysis session should be avoided.1

Geriatric Use

The manufacturer makes no specific dosage recommendations for raltegravir in geriatric patients, but recommends careful dosage selection because of possible age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1

Contraindications

• None.1

Warnings/Precautions

Severe Skin and Hypersensitivity Reactions

Severe, potentially life-threatening skin reactions, including some fatalities, have been reported in patients receiving raltegravir.1 Such reactions have included Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and, occasionally, organ dysfunction including hepatic failure.1

Discontinue raltegravir immediately if signs or symptoms of severe skin or hypersensitivity reactions occur, including (but not limited to) severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, or angioedema.1 Monitor clinical status, including liver aminotransferases, and initiate appropriate therapy.1

A life-threatening reaction could occur if there is a delay in discontinuing raltegravir and any other suspect agents after the onset of severe rash.1

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients receiving multiple-drug antiretroviral therapy, including raltegravir.1 During the initial phase of treatment, patients whose immune systems respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium, M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jirovecii); such responses may necessitate further evaluation and treatment.1

Autoimmune disorders (e.g., Graves' disease, polymyositis, 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 antiretroviral therapy.1

Phenylketonurics

Each 25- or 100-mg raltegravir chewable tablet contains approximately 0.05 or 0.1 mg of phenylalanine, respectively.1 Phenylalanine can be harmful to patients with phenylketonuria.1

Specific Populations

Pregnancy

The Antiretroviral Pregnancy Registry (APR) monitors pregnancy outcomes in females.1 Healthcare providers should register patients at 800-258-4263.1

Available data from the APR show no difference in the rate of overall birth defects in infants of pregnant females receiving raltegravir compared with the background rate of major birth defects of 2.7% in the US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP).1

Based on prospective reports from the APR of over 850 exposures to raltegravir during pregnancy resulting in live births (including over 450 exposures in the first trimester), the prevalence of defects in live births was 3.1% following first trimester exposure to raltegravir-containing regimens and 3.7% following second and third trimester exposure to raltegravir-containing regimens. 1

In animal reproduction studies (rats and rabbits), there was no evidence of adverse developmental outcomes when raltegravir was given orally during organogenesis at doses producing exposures approximately 4 times those reported with the maximum recommended human dose of 1.2 g.1

In animal studies, raltegravir has been shown to cross the placenta with fetal plasma concentrations 1.5-2.5 times greater than in maternal plasma in rats and 2% of maternal plasma concentrations in rabbits on gestation day 20.1

There are limited data on the use of raltegravir 1.2 g (two 600-mg film-coated tablets) once daily in pregnant females.1

Lactation

There are no data available regarding the presence of raltegravir in human milk, the effects on the breastfed infant, or the effects on milk production.1 The drug is distributed into milk in rats; milk concentrations approximately 3 times higher than maternal plasma concentrations were reported at 2 hours after a dose on lactation day 14 in rats receiving oral raltegravir from gestation day 6 to lactation day 14.1

Because of both the potential for HIV-1 transmission (in HIV-negative infants), developing viral resistance (in infants who are HIV-positive), and adverse reactions in breastfed infants similar to those seen in adults, instruct mothers not to breastfeed if they are taking raltegravir.1 The Centers for Disease Control and Prevention recommend that mothers with HIV-1 infection not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.1

Pediatric Use

Raltegravir (Isentress^®; 400-mg film-coated tablets) is indicated for use in pediatric patients weighing 2 kg or more and is not recommended in preterm neonates or pediatric patients weighing less than 2 kg.1

Raltegravir (Isentress^®HD; 600-mg film-coated tablets) is indicated for use in pediatric patients weighing 40 kg or more.1 Although this formulation has not been studied in pediatric patients, the manufacturer states that population pharmacokinetic modeling and simulation support the use of the once-daily regimen (two 600-mg film-coated tablets once daily) in those weighing 40 kg or more.1

Safety and pharmacokinetics of raltegravir for oral suspension were evaluated in 42 full-term HIV-1 exposed neonates at high risk of acquiring HIV-1 infection in a phase 1, open-label, multicenter, clinical trial (IMPAACT P1110).1 The safety profile of the drug in these neonates was comparable to that observed in adults receiving the drug.1

Safety, efficacy, and pharmacokinetics of twice-daily raltegravir were evaluated in HIV-1 infected pediatric patients 4 weeks to 18 years of age in an open-label, multicenter, clinical trial (IMPAACT P1066).1 The safety profile of the drug in these pediatric patients was comparable to that observed in adults receiving the drug.1

Geriatric Use

Experience in adults 65 years of age and older is insufficient to determine whether they respond differently to raltegravir than younger adults.1 Reported clinical experience has not identified differences in response between elderly and younger subjects.1

Raltegravir should be used with caution in geriatric patients because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.1

Hepatic Impairment

Pharmacokinetics of a single 400-mg dose of raltegravir are not altered in adults with moderate hepatic impairment (Child-Pugh score 7-9).1 Pharmacokinetics of the drug have not been studied in patients with severe hepatic impairment.1

Dosage adjustment in patients with mild to moderate hepatic impairment is not required. 1

A once-daily raltegravir regimen is not recommended in patients with hepatic impairment since the pharmacokinetics of the once-daily regimen (two 600-mg film-coated tablets once daily) have not been studied in such patients.1

Patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection may be at increased risk for further elevations in hepatic enzyme concentrations.1

Renal Impairment

Pharmacokinetics of a single 400-mg dose of raltegravir are not altered in adults with severe renal impairment (creatinine clearance less than 30 mL/minute per 1.73 m²).1

Pharmacokinetics of a once-daily raltegravir regimen (two 600-mg film-coated tablets once daily) have not been evaluated in patients with renal impairment.1

Because renal clearance is a minor elimination pathway for unchanged raltegravir, dosage of raltegravir (once or twice daily) does not need to be adjusted in patients with any degree of renal impairment.1

The extent to which raltegravir is removed by dialysis is not known; administration of the drug before a dialysis session should be avoided.1

Common Adverse Effects

Adverse effects reported in 2% or more of patients receiving raltegravir in conjunction with other antiretrovirals include insomnia, headache, dizziness, nausea, and fatigue.1 Creatine kinase elevations, myopathy, and rhabdomyolysis have been reported.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Raltegravir is not a substrate for cytochrome P-450 (CYP) isoenzymes.1

In vitro studies indicate that raltegravir does not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 and does not induce CYP1A2, 2B6, or 3A4.1

Pharmacokinetic interactions are unlikely with drugs that are substrates for these isoenzymes.1

Drugs Affecting or Metabolized by Uridine Diphosphate-glucuronosyltransferases

Raltegravir is primarily metabolized by uridine diphosphate-glucuronosyltransferase (UGT) 1A11

Pharmacokinetic interactions are possible with drugs that are potent inducers of UGT1A1 (decreased plasma concentrations of raltegravir)1 or with inhibitors of UGT1A1 (increased plasma concentrations of raltegravir).1

In vitro studies indicate that raltegravir does not inhibit UGT1A1 or 2B7.1

Drugs Affected by P-glycoprotein Transport

Raltegravir does not inhibit P-glycoprotein (P-gp).1

Anticonvulsants

Carbamazepine

The effects of carbamazepine on the pharmacokinetics of raltegravir are not known.1 Concomitant use of carbamazepine and raltegravir is not recommended.1

Phenobarbital or Phenytoin

The effects of phenobarbital or phenytoin on raltegravir are unknown.1 Concomitant use with these anticonvulsants is not recommended.

Antilipemic Agents

Myopathy, increased creatine kinase, and rhabdomyolysis have been reported with raltegravir use.1 Interactions between antilipemic agents such as statins or fibrates and raltegravir have not been evaluated.1 However, the manufacturer advises caution with concomitant use of raltegravir and agents known to cause these conditions.1

Antimycobacterial Agents

Rifampin

There is a pharmacokinetic interaction between rifampin and raltegravir (decreased raltegravir plasma concentrations and area under the plasma concentration-time curve [AUC]); rifampin is a potent inducer of UGT1A1.1

If raltegravir (twice daily) is used in adults receiving rifampin, raltegravir dosage should be increased to 800 mg twice daily.1 Data are insufficient to make dosage recommendations for concomitant use of raltegravir and rifampin in patients younger than 18 years of age.1

Concomitant use of raltegravir (once daily) and rifampin is not recommended.1

Antiretroviral Agents

HIV Entry and Fusion Inhibitors

Enfuvirtide

There is no in vitro evidence of antagonistic antiretroviral effects between raltegravir and enfuvirtide.1

HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

There is no in vitro evidence of antagonistic antiretroviral effects between raltegravir and NNRTIs.1

Efavirenz

Pharmacokinetic interactions between efavirenz and raltegravir (decreased plasma concentrations and AUC of raltegravir); not considered clinically meaningful.1

Dosage adjustments are not needed if raltegravir is used concomitantly with efavirenz.1

Etravirine

In a pharmacokinetic evaluation, etravirine decreased raltegravir plasma concentrations and AUC; however, the interaction is not considered clinically important.1 Raltegravir does not have a clinically important effect on etravirine pharmacokinetics.1

Dosage adjustments are not needed if etravirine is used concomitantly with raltegravir (twice daily).1

Concomitant use of etravirine and raltegravir (once daily) is not recommended.1

HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

There is no in vitro evidence of antagonistic antiretroviral effects between raltegravir and NRTIs.1

Lamivudine

Raltegravir does not have a clinically important effect on the pharmacokinetics of lamivudine.1 Dosage adjustments are not needed if lamivudine and raltegravir are used concomitantly.1

Tenofovir

In a pharmacokinetic evaluation, tenofovir disoproxil fumarate (DF) increased raltegravir plasma concentrations and AUC; however, the interaction is not considered clinically important.1 Raltegravir does not have a clinically important effect on tenofovir DF pharmacokinetics.1 Dosage adjustments are not needed if raltegravir is used concomitantly with tenofovir DF.1

Pharmacokinetic interactions between raltegravir and tenofovir alafenamide fumarate are not expected.1

HIV Protease Inhibitors (PIs)

There is no in vitro evidence of antagonistic antiretroviral effects between raltegravir and HIV PIs.1

Atazanavir

Pharmacokinetic interactions between raltegravir and ritonavir-boosted atazanavir or unboosted atazanavir (increased raltegravir plasma concentrations and AUC) are not considered clinically important.1

Dosage adjustments are not needed if raltegravir is used concomitantly with ritonavir-boosted atazanavir, or unboosted atazanavir.1

Darunavir

No clinically important pharmacokinetic effects occurred in studies of coadministration of raltegravir with ritonavir-boosted darunavir.1 Raltegravir has no clinically important effect on pharmacokinetics of ritonavir-boosted darunavir.1

Dosage adjustments are not needed if raltegravir is used concomitantly with ritonavir-boosted darunavir.1

Tipranavir

The pharmacokinetic interaction between raltegravir and ritonavir-boosted tipranavir (decreased raltegravir plasma concentrations and AUC) is not considered clinically important.1

Dosage adjustments are not needed if raltegravir (twice daily) is used concomitantly with ritonavir-boosted tipranavir.1

Concomitant use of raltegravir (once daily) and ritonavir-boosted tipranavir is not recommended.1

Benzodiazepines

Raltegravir does not have a clinically important effect on the pharmacokinetics of midazolam.1

Estrogens and Progestins

Ethinyl Estradiol and Norgestimate

Raltegravir does not have a clinically important effect on the pharmacokinetics of hormonal contraceptives containing ethinyl estradiol or norgestimate.1

Dosage adjustments are not needed if oral contraceptives containing ethinyl estradiol and norgestimate are used in patients receiving raltegravir.1

GI Drugs

Antacids

Antacids containing aluminum and/or magnesium administered concomitantly with or 2, 4, or 6 hours before or after a 400-mg raltegravir dose in individuals receiving a twice-daily raltegravir regimen resulted in decreased raltegravir peak plasma concentrations and AUC.1 Similar effects on raltegravir peak plasma concentrations and AUC were reported when antacids containing aluminum and/or magnesium were administered 12 hours after a single 1.2-g raltegravir dose.1 Aluminum- and/or magnesium-containing antacids should not be used in patients receiving raltegravir.1

Concomitant use of antacids containing calcium carbonate in individuals receiving raltegravir (twice daily) resulted in decreased raltegravir peak plasma concentrations and AUC.1 Dosage adjustments are not needed if calcium carbonate-containing antacids are used concomitantly with raltegravir (twice daily).1 Concomitant use of calcium carbonate antacids and raltegravir (once daily) is not recommended.1

Proton Pump Inhibitors

Pharmacokinetic interactions between omeprazole and raltegravir (increased raltegravir peak plasma concentrations and AUC) is not considered clinically important.1

Dosage adjustments are not needed if raltegravir is used concomitantly with omeprazole.1

Opiates and Opiate Partial Agonists

Methadone

Raltegravir does not have a clinically important effect on the pharmacokinetics of methadone; dosage adjustments are not needed if raltegravir is used concomitantly with methadone.1

Description

Raltegravir potassium, an antiretroviral agent, is a human immunodeficiency virus (HIV) integrase strand transfer inhibitor (INSTI).1 200 Raltegravir inhibits the activity of HIV integrase, an enzyme that integrates HIV DNA into the host cell genome.1 Integration is required for maintenance of the viral genome and for efficient viral gene expression and replication.1 Inhibition of integration prevents propagation of viral infection.1 Raltegravir is active against HIV type 1 (HIV-1) and also has some in vitro activity against HIV type 2 (HIV- 2).1,200

Raltegravir-resistant HIV-1 have been produced in vitro and have emerged during raltegravir therapy.1,17,18 Amino acid substitutions in HIV-1 integrase conferring resistance to raltegravir generally also confer resistance to elvitegravir.1 Substitutions at amino acid Y143 confer greater reductions in susceptibility to raltegravir than to elvitegravir, and the E92Q substitution confers greater reductions in susceptibility to elvitegravir than to raltegravir.1 Viruses harboring a substitution at amino acid Q148, along with one or more other raltegravir resistance substitutions, may also have clinically significant resistance to dolutegravir.1

Following oral administration of 400 mg of raltegravir as film-coated tablets in fasting adults, peak plasma concentrations of the drug are attained approximately 3 hours after dosing.1 Following oral administration of raltegravir in a dosage of 1.2 g once daily (two 600-mg film-coated tablets once daily) in fasting individuals, peak plasma concentrations of the drug are attained approximately 1.5-2 hours after a dose.1 Although absolute bioavailability of raltegravir has not been established, oral bioavailability is higher with raltegravir chewable tablets or oral suspension compared with the 400-mg film-coated tablets and oral bioavailability of raltegravir 600-mg film-coated tablets is higher than that of the 400-mg film-coated tablets.1 When raltegravir film-coated tablets are used, steady state is attained in 2 days with the twice-daily regimen (400 mg twice daily) or the once- daily regimen (1.2 g once daily), with little or no accumulation with multiple doses.1 Studies using the 400- or 600-mg film-coated tablets and the chewable tablets indicate that food affects peak plasma concentrations and area under the plasma concentration-time curve (AUC) of raltegravir; however, all formulations of the drug may be administered with or without food.1 Raltegravir is approximately 83% bound to plasma protein.1 Raltegravir is metabolized primarily by uridine diphosphate-glucuronosyltransferase (UGT) 1A1.1 Following an oral dose of raltegravir, approximately 51% of the dose is eliminated in feces (as raltegravir) and 32% is eliminated in urine (as raltegravir and raltegravir glucuronide).1 Raltegravir has an apparent terminal half-life of approximately 9 hours.1

Raltegravir is metabolized primarily by UGT1A.1 However, common UGT1A1 polymorphisms do not appear to alter the pharmacokinetics of raltegravir to any clinically important extent.1

In one study in adults, the AUC of raltegravir in those with UGT1A1*28/*28 genotype (associated with reduced activity of UGT1A1) was compared to the AUC of the drug in those with wild-type UGT1A1 genotype and the geometric mean AUC ratio was 1.41.1

In a neonatal clinical trial (IMPAACT P1110), there was no association between apparent clearance of raltegravir and UGT1A1 polymorphisms.1 Dosage recommendations for raltegravir in neonates younger than 4 weeks of age take into consideration the rapidly increasing UGT1A1 activity and drug clearance that occurs from birth to 4 weeks of a UGT1A1 catalytic activity is negligible at birth and matures after birth.1

Advice to Patients

• Inform patients of the critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.1,200
• Advise patients of the importance of using raltegravir in conjunction with other antiretrovirals—not for monotherapy.1
• If using raltegravir film-coated tablets, advise patients of the importance of swallowing whole; raltegravir chewable tablets can be chewed or swallowed whole.1
• Advise patients to not switch between the film-coated tablet, the chewable tablet, or the oral suspension without first consulting a healthcare professional.1
• Inform patients with phenylketonuria that the chewable tablets contain phenylalanine.1
• If using raltegravir for oral suspension, advise parents and/or caregivers of the importance of reading the manufacturer's instructions for use before preparing and administering the drug.1 Instruct parents and/or caregivers that the oral suspension should be administered within 30 minutes of mixing.1
• If a dose of raltegravir is missed, take the dose as soon as it is remembered and the next dose at the regularly scheduled time.1 If a dose is skipped, do not take a double dose to make up for the missed dose.1
• Advise patients that a severe and potentially life-threatening rash has been reported with use.1 Importance of immediately discontinuing raltegravir and other suspect agents and seeking medical attention if rash occurs and is associated with fever, generally ill feeling, extreme tiredness, muscle or joint aches, breathing difficulty, blisters, oral lesions, eye inflammation, swelling of the face, eyes, lips, or mouth, and/or signs and symptoms of liver problems (e.g., yellowing of skin or whites of the eyes, dark or tea-colored urine, pale stools/bowel movements, nausea, vomiting, loss of appetite, or pain, aching, or sensitivity on the right side below ribs).1
• Advise patients to inform clinician if patient has a history of rhabdomyolysis, myopathy, or increased serum creatine kinase concentrations or is receiving drugs known to cause these conditions (e.g., hydroxymethylglutaryl-CoA [HMG-CoA] reductase inhibitors [statins], fenofibrate, gemfibrozil).1 Instruct patients to immediately inform their clinician if unexplained muscle pain, tenderness, or weakness occurs while receiving raltegravir.1
• Advise patients that signs and symptoms of inflammation from previous infections may occur soon after initiation of antiretroviral therapy in some individuals.1 Advise patients of the importance of immediately informing clinicians if any signs or symptoms of infection occur.1
• Advise patients that raltegravir may interact with some drugs and to inform clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal products, as well as any concomitant illnesses.1
• Advise females of child bearing age to inform clinicians if they are or plan to become pregnant.1 Inform females of child bearing age that there is a pregnancy registry that monitors pregnancy outcomes in females exposed to raltegravir during pregnancy.1
• Advise HIV-infected females not to breast-feed.1
• Advise patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Only references cited for selected revisions after 1984 are available electronically.

1. Merck Sharp & Dohme. Isentress (raltegravir) film-coated tablets, chewable tablets, and granules for oral suspension and Isentress HD (raltegravir) film-coated tablets prescribing information. Rahway, NJ; 2022 May.

2. Steigbigel RT, Cooper DA, Teppler H et al. Long-term efficacy and safety of Raltegravir combined with optimized background therapy in treatment-experienced patients with drug-resistant HIV infection: week 96 results of the BENCHMRK 1 and 2 Phase III trials. Clin Infect Dis. 2010; 50:605-12. [Web]

14. Steigbigel RT, Cooper DA, Kumar PN et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med . 2008; 359:339-54. [Web]

15. Nachman S, Zheng N, Acosta EP et al. Pharmacokinetics, safety, and 48-week efficacy of oral raltegravir in HIV-1-infected children aged 2 through 18 years. Clin Infect Dis. 2013; :.

17. Rockstroh JK, DeJesus E, Lennox JL et al. Durable efficacy and safety of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected patients: final 5-year results from STARTMRK. J Acquir Immune Defic Syndr. 2013; 63:77-85.

18. Eron JJ, Cooper DA, Steigbigel RT et al. Efficacy and safety of raltegravir for treatment of HIV for 5 years in the BENCHMRK studies: final results of two randomised, placebo-controlled trials. Lancet Infect Dis . 2013; 13:587-96.

24. Cahn P, Sax PE, Squires K et al. Raltegravir 1200 mg Once Daily vs 400 mg Twice Daily, With Emtricitabine and Tenofovir Disoproxil Fumarate, for Previously Untreated HIV-1 Infection: Week 96 Results From ONCEMRK, a Randomized, Double-Blind, Noninferiority Trial. J Acquir Immune Defic Syndr . 2018; 78:589-598. [Web]

25. Raffi F, Babiker AG, Richert L et al. Ritonavir-boosted darunavir combined with raltegravir or tenofovir- emtricitabine in antiretroviral-naive adults infected with HIV-1: 96 week results from the NEAT001/ANRS143 randomised non-inferiority trial. Lancet . 2014; 384:1942-51. [Web]

26. Taiwo B, Zheng L, Gallien S et al. Efficacy of a nucleoside-sparing regimen of darunavir/ritonavir plus raltegravir in treatment-naive HIV-1-infected patients (ACTG A5262). AIDS . 2011; 25:2113-22. [Web]

27. João EC, Morrison RL, Shapiro DE et al. Raltegravir versus efavirenz in antiretroviral-naive pregnant women living with HIV (NICHD P1081): an open-label, randomised, controlled, pase 4 trial. Lancet HIV . 2020; 7:e322-e331. doi: 10.1016/S2352-3018(20)30038-2

28. McAllister J, Read P, McNulty A, Tong WWY, Ingersoll A, Carr A. Raltegravir-emtricitabine-tenofovir as HIV nonoccupational post-exposure prophylaxis in men who have sex with men: safety, tolerability and adherence. HIV Med. 2014; 15:13-22. doi: 10.1111/hiv.12075

29. Mayer KH, Mimiaga MJ, Gelman M, Grasso C. Raltegravir, tenofovir DF, and emtricitabine for postexposure prophylaxis to prevent the sexual transmission of HIV: safety, tolerability, and adherence. J Acquir Immune Defic Syndr . 2012; 59:354-9. doi: 10.1097/QAI.0b013e31824a03b8

198. Centers for Disease Control and Prevention. Updated guidelines for antiretroviral postexposure prophylaxis after sexual, injection drug use, or other nonoccupational exposure to HIV - United States, 2016. From CDC.gov website. [Web]

199. Kuhar DT, Henderson DK, Struble KA et al. Updated US Public Health Service guidelines for the management of occupational exposures to human immunodeficiency virus and recommendations for postexposure prophylaxis. Infect Control Hosp Epidemiol . 2013; 34:875-92.

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (March 23, 2023). Updates may be available at HIV.gov website. [Web]

201. Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in pediatric HIV infection (January 31, 2023). Updates may be available at HIV.gov [Web]

202. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, US Department of Health and Human Services (HHS). Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States (January 31, 2023). Updates may be available at HIV.gov [Web]