ISENTRESS

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific 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 the 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.



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. Administer the dose orally within 30 minutes of mixing.
-Discard any remaining suspension.

Adverse events in pediatric clinical trials of raltegravir were comparable to those observed in adults.

During adult clinical trials, 1% to 3% of patients receiving raltegravir as part of a combination regimen experienced nausea. Other gastrointestinal adverse reactions reported in less than 2% of patients receiving the drug included abdominal pain, dyspepsia, vomiting, and gastritis. Diarrhea has also occurred in postmarketing reports.

Neurologic adverse reactions have been observed during clinical trials. Headache was reported in 1% to 4% of adult patients receiving raltegravir along with optimized background therapy (OBT). Additionally, dizziness was noted in 2% or less of adult patients who received raltegravir in a combination regimen.

Fatigue (2%) and asthenia (less than 2%) were reported by adult patients receiving raltegravir as part of a combination regimen during clinical trials.

Hematologic adverse reactions were reported during adult clinical trials. Anemia (hemoglobin concentration less than 8.5 gm/dL) was reported in 1% or less of adult raltegravir-treated patients. Neutropenia was also reported with an overall incidence of 1% to 4% in adults. Neutropenia was classified as Grade 2 (750 to 999 cells/mm3, 2% to 4%), Grade 3 (500 to 749 cells/mm3, 1% to 3%), and Grade 4 (less than 500 cells/mm3, 1% or less) decreases in absolute neutrophil counts. Grade 2 to 4 decreases in platelet counts (platelet count of 99.9 x 103 cells/mm3 or less) occurred in 0% to 3% of adult patients, with thrombocytopenia (platelet count less than 50 x 103 cells/mm3) being noted in 1% or less of adult raltegravir recipients.

Of treatment-experienced adult patients who received raltegravir with optimized background therapy, 2% had a serum creatine kinase concentration of 6 to 9.9 times the upper limit of normal (x ULN), 4% had a serum creatine kinase concentration of 10 to 19.9x ULN, and 3% had a serum creatine kinase concentration of at least 20x ULN. Myopathy and rhabdomyolysis have been reported; however, the relationship of raltegravir to these events is not known. Raltegravir should be used cautiously in patients at increased risk of myopathy or rhabdomyolysis, such as patients taking concomitant medications known to cause these conditions.

Renal failure (unspecified) and nephrolithiasis were reported in less than 2% of adult patients who received raltegravir as part of a combination regimen during clinical trials.

Raltegravir may cause hyperglycemia. Elevated fasting blood glucose concentrations were observed in 2% to 10% of adult patients who received raltegravir as part of a combination regimen during clinical trials. The majority of patients who experienced elevated fasting glucose concentrations had values ranging between 126 to 250 mg/dL; no raltegravir-treated patient developed a fasting glucose concentration of more than 500 mg/dL. Adverse events in pediatric clinical trials were comparable to those observed in adults.

Raltegravir may cause hyperamylasemia. Of treatment-experienced adult patients who received raltegravir with optimized background therapy, 2% had a serum amylase concentration 1.6 to 2 times the upper limit of normal (x ULN), 4% had a concentration of 2.1 to 5x ULN, and less than 1% had a concentration more than 5x ULN. Serum lipase concentrations were also elevated in treatment-experienced patients, with 5% of adults experiencing an increase to 1.6 to 3x ULN and 2% experiencing a 3.1 to 5x ULN increase.

Less than 2% of adult patients who received raltegravir in combination with other antiretroviral agents during clinical trials developed an infection. Specific infections included genital herpes and herpes zoster.

In a pediatric trial of 126 patients, 1 pediatric patient experienced elevated hepatic enzymes manifesting as a Grade 4 increase in AST and a Grade 3 increase in ALT. Hepatitis was reported in less than 2% of adult patients during clinical trials. Adult patients with chronic (but not acute) active hepatitis B (HBV) or hepatitis C (HCV) coinfection were allowed to enroll as long as their baseline liver function tests did not exceed 5-times the upper limit of normal. Although the safety profile in coinfected patients was similar to patients without HBV or HCV coinfection, the incidence of elevated hepatic enzymes and hyperbilirubinemia was higher in the HBV and HCV subgroups. In a 96-week clinical trial of treatment-experienced patients, Grade 2 or higher increases in AST, ALT, and total bilirubin occurred in 29%, 34%, and 13%, respectively, of patients with HBV or HCV coinfection, compared with 11%, 10%, and 9%, respectively, of patients without coinfection. Similarly, in treatment-naive patients receiving 240 weeks of raltegravir 400 mg twice daily, increases in AST, ALT, and bilirubin were observed in 22%, 44%, and 17%, respectively, of patients with HBV or HCV coinfection, compared with 13%, 13%, and 5% in patients without coinfection. In treatment-naive patients who received 48 weeks of raltegravir 1,200 mg once daily, increases in AST, ALT, and bilirubin were observed in 27%, 40%, and 13%, respectively, of patients with HBV or HCV coinfection, compared with 7%, 5%, and 3% in patients without coinfection. 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. Grade 2 to 4 increases in alkaline phosphatase have occurred in up to 2% of patients in raltegravir trials overall. Hepatic failure, with and without associated hypersensitivity, has been reported postmarketing. According to the manufacturer, hepatic failure occurred in persons with either underlying hepatic disease and/or persons receiving concomitant medications.

One pediatric patient in clinical trials (total n = 126) reported Grade 3 psychomotor hyperactivity, abnormal behavior, and insomnia. Insomnia was reported in 4% or less of adults receiving raltegravir in combination with other antiretroviral agents during clinical trials. Depression, including suicidal ideation and behaviors, was noted in less than 2% of adult patients during clinical trials, and particularly in patients with a preexisting history of psychiatric illness. Anxiety and paranoia have been reported postmarketing.

Rash (unspecified) has been associated with raltegravir treatment. In some cases, rash may be part of a serious reaction. Failure to recognize and stop raltegravir after the onset of severe rash may result in a life-threatening reaction. In a clinical trial of 126 children 2 years and older, one child experienced a Grade 2 drug-related rash, and in another trial (n = 26, 4 weeks to less than 2 years of age), 1 patient experienced a Grade 3 serious rash that required therapy discontinuation. Episodes of severe, sometimes fatal, dermatologic reactions have been associated with the use of raltegravir during the postmarketing period. These reports include cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction. Health care providers are advised to monitor clinical status, initiate appropriate therapy, and immediately discontinue raltegravir in any patient displaying signs or symptoms of severe skin or hypersensitivity reactions including severe rash or rash accompanied by fever, malaise, fatigue, arthralgia, myalgia, blisters, oral ulceration, conjunctivitis, facial edema, hepatitis, eosinophilia, or angioedema.

Unplanned raltegravir therapy interruption may be necessary in specific situations such as serious drug toxicity, intercurrent illness or surgery precluding oral intake (e.g., gastroenteritis or pancreatitis), or drug non-availability. If short-term treatment interruption is necessary (i.e., less than 1 to 2 days), in general, it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption is because of 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. When the antiretroviral regimen contains drugs with differing half-lives, stopping all drugs simultaneously may result in functional monotherapy of the drug with the longest half-life. For example, after discontinuation, the duration of detectable drug concentrations of efavirenz and nevirapine ranges from less than 1 week to more than 3 weeks. Simultaneously stopping all drugs in a regimen containing these agents may result in functional monotherapy with the NNRTI and may increase the risk of NNRTI-resistant mutations. 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.

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. 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 results kept in the patient's medical record until they become 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.

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. In addition to patients with severe hepatic impairment, cautious administration is also recommended for patients with hepatitis. In general, the safety profile of raltegravir in subjects with hepatitis B and/or hepatitis C virus coinfection is similar to subjects without hepatitis B and/or hepatitis C virus coinfection. However, as compared with data from patients without hepatitis, a higher percentage of patients with chronic, active hepatitis B and/or C and baseline liver function tests not greater than 5 times the upper limit of normal had elevated AST, ALT, or total bilirubin. 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. All patients who present with HIV infection should be screened for hepatitis B virus (HBV) coinfection to assure appropriate treatment. Patients with hepatitis B and HIV coinfection who require treatment for either infection should be started on a fully suppressive antiretroviral (ARV) regimen that contains nucleoside reverse transcriptase inhibitors (NRTIs) with activity against both viruses. Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, or tenofovir as the only active agent) due to the risk of developing resistant strains of HIV. The HIV guidelines recommend that coinfected pediatric patients 2 years of age and older receive an ARV regimen that contains tenofovir in combination with either lamivudine or emtricitabine as the dual NRTI backbone. If tenofovir cannot be used, another agent with anti-HBV activity should be used in combination with lamivudine or emtricitabine to assure adequate treatment of HBV infection. Management of HIV should be continued with the goal of maximal suppression. Hepatitis C virus (HCV) screening should also be performed in any child whose mother is known to have HCV infection and all HIV-infected adolescents. Treatment of HCV infection in pediatric patients younger than 3 years is not usually recommended; however, consider treatment for all children 3 years of age and older and adolescents with hepatitis C and HIV coinfection who have no contraindications to treatment. For ARV-naive adolescent patients with CD4 counts more than 500 cells/mm3, consideration may be given to deferring ARV therapy until the hepatitis C treatment regimen has been completed. Conversely, for adolescent patients with CD4 counts less than 200 cells/mm3, consider delaying initiation of the HCV treatment regimen until the patient is stable on a fully suppressive ARV regimen. All HIV-infected children and adolescents, regardless of HIV and HCV status, should receive standard vaccination with hepatitis A and B vaccines. Additionally, counsel HIV/HCV-coinfected adolescents to avoid alcohol.

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.

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 associated behaviors have been noted in post-marketing reports, particularly in patients with a preexisting history of psychiatric disease.


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 mycobacterium avium complex (MAC), cytomegalovirus (CMV), Pneumocystis jiroveci 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 develop; the time to onset is variable and may occur months after treatment initiation.

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 may result in a life-threatening reaction.

Description: Raltegravir is an antiretroviral agent for the treatment of human immunodeficiency virus (HIV) infection. It is the first in a class of antiretrovirals called HIV integrase strand transfer inhibitors, which are designed to slow the advancement of HIV infection by blocking the HIV integrase enzyme needed for viral multiplication. The use of other active agents with raltegravir is associated with a greater likelihood of treatment response. Creatine phosphokinase (CPK) elevation, muscle weakness, and rhabdomyolysis have been reported with the use. The film-coated tablets are not interchangeable with the chewable tablets or oral suspension. Raltegravir is FDA-approved for use in pediatric patients as young as term neonates weighing at least 2 kg.

NOTE: The 400 mg and 600 mg film-coated tablets are not bioequivalent with 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.

Initiation of HIV therapy
-Antiretroviral drug resistance testing (preferably genotypic testing) is recommended prior to initiation of therapy in antiretroviral treatment (ART)-naive patients and prior to changing therapy for treatment failure.
-Initiation of treatment immediately or within days after HIV diagnosis is recommended in all pediatric patients, except for patients with cryptococcal meningitis, disseminated Mycobacterium avium complex disease, or Mycobacterium tuberculosis disease. In these patients, initiate treatment for the opportunistic infection first, ahead of ART initiation. The urgency of rapid treatment initiation is especially critical for all patients younger than 1 year, who carry the highest risk of rapid disease progression and mortality. If therapy is deferred for certain circumstances, closely monitor the patient's virologic, immunologic, and clinical status at least every 3 to 4 months. If therapy is deferred, initiate treatment when HIV RNA concentrations increase, CD4 count or percentage values decline (i.e., approaching CDC Stage 2 or 3), the patient develops new HIV-related clinical symptoms, or the ability of the caregiver and patient to adhere to the prescribed regimen has improved.

Place in therapy for HIV
-Raltegravir is used as part of a 3-drug combination antiretroviral regimen with zidovudine and lamivudine at treatment doses for the prevention of perinatal HIV transmission in neonates with presumed HIV exposure or those at high risk for perinatal HIV transmission (i.e., mother has not received antepartum antiretroviral therapy). Raltegravir, administered with 2 nucleoside reverse transcriptase inhibitors (NRTIs), is also a preferred regimen if HIV treatment initiation is planned in neonates prior to 14 days of age (37 weeks postmenstrual age and older and weighing at least 2 kg).
-Raltegravir plus a 2-NRTI backbone option is recommended as a preferred integrase strand transfer inhibitor (INSTI)-based regimen for initial therapy for treatment-naive infants younger than 4 weeks weighing at least 2 kg. Raltegravir plus a 2-NRTI backbone option is an alternative INSTI-based regimen in infants and children 4 weeks and older.
-In certain clinical situations, raltegravir plus a 2-NRTI backbone option is a preferred initial regimen for treatment-naive adolescents. Raltegravir plus darunavir/ritonavir is also a regimen that may be used as initial therapy in treatment-naive adolescents unable to take abacavir or tenofovir (if HIV RNA is less than 100,000 copies/mL, CD4 is more than 200 cells/mm3, and without HBV coinfection).

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: human immunodeficiency virus (HIV)
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

For the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents:
Oral dosage (powder for suspension):
Term Neonates 0 to 7 days weighing 2 kg: 4 mg 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 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 4 kg: 7 mg 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 older than 7 days weighing 2 kg: 8 mg PO twice daily (approximately 3 mg/kg/dose).
Term Neonates older than 7 days weighing 3 kg: 10 mg PO twice daily (approximately 3 mg/kg/dose).
Term Neonates older than 7 days weighing 4 kg: 15 mg PO twice daily (approximately 3 mg/kg/dose).
Infants 4 weeks and older weighing 3 kg: 25 mg PO twice daily.
Infants 4 weeks and older weighing 4 to 5 kg: 30 mg PO twice daily.
Infants and Children 4 weeks and older weighing 6 to 7 kg: 40 mg PO twice daily.
Infants and Children 4 weeks and older weighing 8 to 10 kg: 60 mg PO twice daily.
Infants and Children 4 weeks and older weighing 11 to 13 kg: 80 mg PO twice daily.
Children weighing 14 to 19 kg: 100 mg PO twice daily.
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.
Children weighing 11 to 13 kg: 75 mg PO twice daily.
Children weighing 14 to 19 kg: 100 mg PO twice daily.
Children weighing 20 to 27 kg: 150 mg PO twice daily.
Children and Adolescents weighing 28 to 39 kg: 200 mg PO twice daily.
Children and Adolescents weighing 40 kg or more: 300 mg PO twice daily.
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.
Children and Adolescents weighing 25 kg or more: 400 mg PO twice daily.
Oral dosage (600 mg film-coated tablet):
Children and Adolescents weighing 40 kg or more: 1,200 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. While modeling and simulations for pediatric patients indicate that pharmacokinetic targets are met using the once-daily raltegravir HD regimen, there are no clinical data on the use of this dose in children weighing less than 50 kg.

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):
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 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.
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 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 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 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.

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 either nevirapine or raltegravir at treatment doses, is 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) and neonates born to HIV-infected mothers who have not received antepartum ARV treatment, who have received only intrapartum ARV treatment, who have suboptimal viral suppression (defined as at least 2 consecutive tests with HIV RNA less than 50 copies/mL obtained at least 4 weeks apart within 4 weeks of delivery), or who have acute or primary HIV infection during pregnancy or breastfeeding. Consider raltegravir use in the 3-drug combination ARV prophylaxis regimen if the mother has HIV-1 and HIV-2 infection, since HIV-2 is not susceptible to nevirapine.
NOTE: The ARV regimen for newborns born to mothers with known or suspected drug resistance should be determined in consultation with a pediatric HIV specialist before delivery or through consultation via the National Perinatal HIV hotline (1-888-448-8765). Additionally, no evidence exists that shows that neonatal prophylaxis regimens customized based on presence of maternal drug resistance are more effective than standard neonatal prophylaxis regimens.
Oral dosage (powder for suspension):
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. To minimize dosing changes during outpatient use, some experts increase to 3 mg/kg/dose twice daily upon discharge on day 4 or 5 of life. 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, including breastfeeding. 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.
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. To minimize dosing changes during outpatient use, some experts increase to 3 mg/kg/dose twice daily upon discharge on day 4 or 5 of life. 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, including breastfeeding. 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.
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. To minimize dosing changes during outpatient use, some experts increase to 3 mg/kg/dose twice daily upon discharge on day 4 or 5 of life. 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, including breastfeeding. 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.
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, including breastfeeding. 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.
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, including breastfeeding. 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.
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, including breastfeeding. 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.
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, including breastfeeding. 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.
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, including breastfeeding. 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.
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, including breastfeeding. 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.

Therapeutic Drug Monitoring:
Suggested target trough concentration: 65 ng/mL
-Routine monitoring of plasma concentrations of antiretroviral (ARV) drugs is generally not recommended in HIV-infected pediatric patients. However, therapeutic drug monitoring may be considered in the following situations :-use of drugs with limited pharmacokinetic data and/or therapeutic experience in pediatric patients
-use of drugs with significant food and/or drug interactions
-suboptimal treatment response
-suspected suboptimal absorption, distribution, metabolism, or elimination of the drug
-suspected concentration-dependent drug-associated toxicity
-use of alternative dosing regimens and ARV combinations for which safety and efficacy have not been established in clinical trials
-heavily pretreated patients experiencing virologic failure and who may have viral isolates with reduced susceptibility to ARVs

-Geometric mean trough concentrations have ranged from 71 to 333 ng/mL in clinical trials of raltegravir in pediatric patients. In a major pharmacokinetic study (IMPAACT P1066) in 96 children (2 to 18 years), the target raltegravir trough concentration was greater than 33 ng/mL, which is the in vitro concentration at which 95% of virologic replication is inhibited for antiviral activity. Higher trough concentrations have also been observed with the film-coated tablets compared with the chewable tablets (233 to 246 ng/mL vs. 113 to 130 ng/mL) in pediatric clinical studies.

Maximum Dosage Limits:
-Neonates
Premature and Term Neonates weighing less than 2 kg: Safety and efficacy 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.
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 4 kg: 7 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 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 4 kg: 30 mg/day PO for the oral suspension; safety and efficacy of other formulations have not been established.
-Infants
weight 3 kg: 50 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 6 to 7 kg: 80 mg/day PO for the oral suspension; safety and efficacy of other formulations have not been established.
weight 8 to 10 kg: 120 mg/day PO for the oral suspension; safety and efficacy of other formulations have not been established.
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.
-Children
weight 8 to 10 kg: 120 mg/day PO for the oral suspension; safety and efficacy of other formulations have not been established.
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 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 20 to 24 kg: 300 mg/day PO for the chewable 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 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 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 PO for the 600 mg film-coated tablet; safety and efficacy have not been established for the oral suspension.
-Adolescents
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 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 PO for the 600 mg film-coated tablet; safety and efficacy have not been established for the oral suspension.

Patients with Hepatic Impairment Dosing
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.

Patients with Renal Impairment Dosing
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.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Raltegravir inhibits the catalytic activity of HIV integrase, which is an HIV encoded enzyme required for viral replication. Integrase is one of the three HIV-1 enzymes required for viral replication. Integration of HIV into cellular DNA is a multistep 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, thus, 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 phosphoryltransferases including DNA polymerases alpha, beta, and gamma.

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 occurs mainly by metabolism via a UDP-glucuronosyltransferases (UGT)1A1-mediated glucuronidation pathway. Data are not sufficient to determine the impact of UGT1A1 polymorphism on pharmacokinetic parameter values. The terminal half-life in children and adolescents is approximately 4 to 5 hours, which is shorter than the half-life of 9 hours observed in adults. 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 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 or inhibit UGT1A1, UGT2B7, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A. Also, it does not inhibit P-glycoprotein (P-gp)-mediated transport. Raltegravir is not a substrate of CYP enzymes.


-Route-Specific Pharmacokinetics
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.


-Special Populations
Pediatrics
Term Neonates
Raltegravir is eliminated primarily through UGT1A1-mediated glucuronidation. UGT1A1 activity in neonates is negligible at birth and matures after birth. Dose recommendations for neonates less than 4 weeks of age take into consideration the rapidly increasing UGT1A1 activity and drug clearance from birth to 4 weeks of age.

In the IMPAACT P1110 Study, the following PK parameters were calculated :
Birth through 48 hours
Oral suspension: n = 25, approximate dose = 1.5 mg/kg once daily
-geometric mean AUC = 85.9 micromole x hour
-geometric mean Cmin = 2,132.9 nanomole
15 to 18 days
Oral suspension: n = 23, approximate dose = 3 mg/kg twice daily
-geometric mean AUC = 32.2 micromole x hour
-geometric mean Cmin = 1,255.5 nanomole

Infants 4 weeks and older, Children, and Adolescents
Based on observations in an adult study of a higher AUC with raltegravir chewable tablets and oral suspension compared with the 400 mg film-coated tablets, the proposed pediatric dosage for the chewable tablets and oral suspension to achieve a similar pharmacokinetic profile as adults receiving 400 mg PO twice daily was determined to be 6 mg/kg/dose PO twice daily. This targeted dose was confirmed in a study of HIV-infected infants, children, and adolescents ages 4 weeks to 18 years (n = 59) in which children weighing 3 to 19 kg received the oral suspension, children weighing 11 to 24 kg received chewable tablets, and children weighing 25 kg or more received either the chewable tablets or film-coated tablets. Differences in exposure were also noted between the formulations in this study. Pediatric patients weighing 25 kg or more given the chewable tablets had lower trough concentrations compared with those given the film-coated tablets (113 ng/mL vs. 233 ng/mL). The lowest trough concentrations (82 ng/mL) were noted in pediatric patients weighing 11 to 24 kg who received the chewable tablets.

In the IMPAACT P1066 Study, the following PK parameters were calculated :
Children 2 to 5 years
Chewable tablet: n = 12, mean dose = 6.2 mg/kg
-Cmin = 39.5 ng/mL (SD = 21.9)
-t1/2 = 4.1 hours (SD = 3.2)
Children 6 to 11 years
Chewable tablet: n = 10, mean dose = 6.5 mg/kg
-Cmin = 78.7 ng/mL (SD = 68.9)
-t1/2 = 4.5 hours (SD = 4.2)
Film-coated tablet: n = 11, mean dose = 13.4 mg/kg
-Cmin = 399.4 ng/mL (SD = 880.9)
-t1/2 = 3.7 hours (SD = 1.4)
Adolescents 12 to 18 years
Film-coated tablet: n = 11, mean dose = 9.3 mg/kg
-Cmin = 197 ng/mL (SD = 154.2)
-t1/2 = 4.9 hours (SD = 3.6)

Hepatic Impairment
No clinically important pharmacokinetic differences were noted between patients with moderate hepatic impairment and patients with normal hepatic function. The effect of severe hepatic impairment on the pharmacokinetics of raltegravir has not been studied.

Renal Impairment
Renal clearance of unchanged raltegravir is a minor pathway of elimination. As expected, no clinically important pharmacokinetic differences were noted between patients with severe renal impairment and patients with normal renal function. Avoid administration before a dialysis session; the extent to which raltegravir may be dialyzable is unknown.

Other
Pharmacogenomics
In the neonatal study, IMPAACT P1110, there was no association between apparent clearance of raltegravir and UGT1A1 genotype polymorphisms.