Raltegravir is an antiretroviral agent approved for the treatment of human immunodeficiency virus (HIV) infection. It was the first in a class of antiretroviral agents called HIV integrase strand transfer inhibitors, which were designed to slow the advancement of HIV infection by blocking the HIV integrase enzyme needed for viral multiplication. As compared with only optimized background therapy (OBT), oral raltegravir 400 mg twice daily plus OBT was significantly more effective at both reducing HIV viral RNA concentrations and increasing CD4 cell counts among treatment-experienced adults with documented resistance to at least one nucleoside reverse transcriptase inhibitor (NRTI), one non-nucleoside reverse transcriptase inhibitor (NNRTI), and one protease inhibitor (PI). In the raltegravir group (n = 462), 55% of patients achieved an HIV viral RNA load less than 50 copies/mL compared with 27% of patients in the only OBT group (n = 237). Virologic failure occurred in 35% of patients in the raltegravir group compared with 66% of patients in the only OBT group. The mean increases in CD4 cell counts from baseline were 118 cells/mm3 for raltegravir recipients and 47 cells/mm3 for recipients of only OBT. The use of other active agents with raltegravir was associated with a greater likelihood of treatment response. In treatment-naive patients, receipt of raltegravir, tenofovir, and lamivudine for 48 weeks led to rapid, potent, and durable reductions in viral load. Creatine phosphokinase (CPK) elevation, muscle weakness, and rhabdomyolysis have been reported with raltegravir therapy.
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 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. The dose should be administered orally within 30 minutes of mixing.
-Discard any remaining suspension.
In raltegravir clinical studies, hypersensitivity reactions were observed in < 2% of patients.
Cancers have been reported in patients receiving treatment with raltegravir as part of a combination regimen during clinical trials. According to the manufacturer, the types and frequencies of these specific cancers were consistent with those expected in a highly immunodeficient patient population. Additionally, these studies did not find an increased risk for cancer in raltegravir-treated patients when compared against the comparator groups.
When compared against baseline values, treatment-naive patients who received 240 weeks of raltegravir in combination with other antiretroviral agents experienced an increase in total cholesterol, HDL cholesterol, and LDL cholesterol of 16, 6, and 10 mg/dL, respectively. In addition, drug recipients had 240 week triglyceride concentrations that were 2 mg/dL higher than baseline level (mean change).
During clinical trials, 3% of patients receiving raltegravir as part of a combination regimen experienced nausea. Other gastrointestinal adverse events reported in less than 2% of patients receiving the drug included abdominal pain, dyspepsia, vomiting, and gastritis. Diarrhea and weight gain have been reported during postmarketing surveillance. Data from postmarketing trials found treatment-naive patients who started an integrase inhibitor-containing regimen (such as raltegravir) gained more weight than patients who began a protease inhibitor- or NNRTI-based regimen. It is unknown whether the increase in weight is reversible upon treatment discontinuation.
Neurologic adverse events have been observed during clinical trials. Headache (2-4%) and dizziness (2%) were reported by patients receiving raltegravir along with optimized background therapy (OBT).
Fatigue (2%) and asthenia (< 2%) were reported by patients receiving raltegravir as part of a combination regimen during clinical trials.
Hematologic adverse events were reported during clinical trials. Anemia (hemoglobin concentrations of less than 8.5 gm/dL) was reported in 1% or less of all raltegravir-treated patients. Neutropenia was also reported with an overall incidence of 1% to 4%. 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 patients, with thrombocytopenia (platelet counts less than 50 x 103 cells/mm3) being noted in 1% or less of raltegravir recipients.
Of treatment-experienced patients who received raltegravir with optimized background therapy, 2% had a serum creatine kinase concentration of 6-9.9 times the upper limit of normal (x ULN), 4% had a serum creatine kinase concentration of 10-19.9x 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 (see Drug Interactions).
Renal failure (unspecified) and nephrolithiasis were reported in < 2% of all 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 2-10% of patients who received it as part of a combination regimen during clinical trials. The majority of patients who experienced elevated fasting glucose concentrations had values ranging between 126-250 mg/dL; no raltegravir-treated patient developed a fasting glucose concentration of > 500 mg/dL.
Raltegravir may cause hyperamylasemia. Of treatment-experienced patients who received raltegravir with optimized background therapy, 2% had a serum amylase concentration 1.6-2 times the upper limit of normal (x ULN), 4% had a concentration of 2.1-5x ULN, and < 1% had a concentration > 5x ULN. Serum lipase concentrations were also elevated in treatment-experienced raltegravir recipients, with 5% experiencing an increase to 1.6-3x ULN and 2% experiencing a 3.1-5x ULN increase.
Less than 2% of patients who received raltegravir in combination with other antiretroviral agents during clinical trials developed an infection. Specific infections experienced by raltegravir recipients included genital herpes and herpes zoster.
Hepatitis was reported in less than 2% of raltegravir recipients during clinical trials. 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 were higher in the HBV and HCV subgroups. In a 96 week clinical trial of treatment-experienced patients, the percentage of drug recipients with Grade 2 or higher laboratory abnormalities that represented a worsening grade from baseline was higher in hepatitis coinfected patients than in patients without coinfection [elevated AST (29% vs 11%), elevated ALT (34% vs 10%), and elevated bilirubin (13% vs 9%)]. 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, compared to 13%, 13%, and 5% in patients without HBV or HCV coinfection. In treatment-naive patients with and without HBV or HCV coinfection who received 48 weeks of raltegravir 1,200 mg once daily, increases in AST, ALT, and bilirubin were (27% vs. 7%), (40% vs. 5%), and (13% vs. 3%), respectively. 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 during postmarketing use of raltegravir. According to the manufacturer, hepatic failure occurred in persons with either underlying hepatic disease or persons receiving concomitant medications.
Insomnia was reported in 4% of treatment-naive patients receiving raltegravir in combination with other antiretroviral agents during clinical trials. Depression, including suicidal ideation and behaviors, was noted in < 2% of all patients during raltegravir trials, and particularly in patients with a preexisting history of psychiatric illness. Anxiety and paranoia have occurred in post-marketing reports. Due to the voluntary nature of post-marketing reports, neither a frequency nor a definitive causal relationship can be established.
During clinical trials, rash (unspecified) was reported in treatment-experienced patients receiving raltegravir in combination with other antiretroviral agents. According to the manufacturer, these rashes were mild to moderate in severity and did not require discontinuation of therapy in affected individuals. In contrast to rashes experienced during clinical trials, episodes of severe, sometimes fatal, dermatologic reactions have been associated with the use of raltegravir during the post-marketing 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. Failure to recognize and stop raltegravir after the onset of severe rash may result in a life-threatening reaction.
During baseline evaluation of people with HIV, discuss risk reduction measures and the need for status disclosure to sexual or needle-sharing partners, especially with untreated patients who are still at high risk of HIV transmission. Include the importance of adherence to therapy to achieve and maintain a plasma HIV RNA less than 200 copies/mL. Maintaining a plasma HIV RNA less than 200 copies/mL, including any measurable value below this threshold, with antiretroviral therapy prevents sexual transmission of HIV to their partners. Patients may recognize this concept as Undetectable = Untransmittable or U=U.[46638 Instruct patients to achieve sustained viral suppression (i.e., 2 recorded measurements of plasma viral loads that are below the limits of detection and taken at least 3 months apart) before attempting to conceive a child in order to maximize their health, prevent HIV sexual transmission, and minimize the risk of HIV transmission to the infant once conception occurs. For partners with different HIV status when the person with HIV is on antiretroviral therapy and has achieved sustained viral suppression, sexual intercourse without a condom allows conception without sexual HIV transmission to the person without HIV. Expert consultation is recommended.
Unplanned antiretroviral therapy interruption may be necessary for specific situations, such as serious drug toxicity, intercurrent illness or surgery precluding oral intake (e.g., gastroenteritis or pancreatitis), severe hyperemesis gravidarum unresponsive to antiemetics, or drug non-availability. If short-term treatment interruption (i.e., less than 1 to 2 days) is necessary, in general, it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption occurs in a pregnant patient or is because of a serious toxicity. However, if a short-term treatment interruption is anticipated in the case of elective surgery, the pharmacokinetic properties and food requirements of specific drugs should be considered; as stopping all simultaneously in a regimen containing drugs with differing half-lives may result in functional monotherapy of the drug with the longest half-life and may increase the risk for resistant mutations. Healthcare providers are advised to reinitiate a complete and effective antiretroviral regimen as soon as possible after an interruption of therapy. Planned long-term treatment interruptions are not recommended due to the potential for HIV disease progression (i.e., declining CD4 counts, viral rebound, acute viral syndrome), development of minor HIV-associated manifestations or serious non-AIDS complications, development of drug resistance, increased risk of HIV transmission, and increased risk for opportunistic infections. If therapy must be discontinued, counsel patient on the potential risks and closely monitor for any clinical or laboratory abnormalities.
HIV treatment guidelines recommend clinicians provide mothers with evidence-based, patient-centered counseling to support shared decision-making regarding infant feeding. Inform patients that use of replacement feeding (i.e., formula or banked pasteurized donor human milk) eliminates the risk of HIV transmission. Advise patients who receive a diagnosis of HIV infection while breast-feeding (acute HIV) to immediately discontinue breast-feeding and switch to replacement feeding in order to reduce the risk of postnatal HIV transmission to the infant. Replacement feeding is also recommended for use when mothers with HIV are not on antiretroviral therapy (ART) or do not have suppressed viral load during pregnancy, as well as at delivery. For patients on ART who have achieved and maintained viral suppression during pregnancy (at minimum throughout the third trimester) and postpartum, the transmission risk from breast-feeding is less than 1%, but not zero. Virologically suppressed mothers who choose to breast-feed should be supported in this decision. If breast-feeding is chosen, counsel the patient about the importance of adherence to therapy and recommend that the infant be exclusively breast-fed for up to 6 months of age, as exclusive breast-feeding has been associated with a lower rate of HIV transmission as compared to mixed feeding (i.e., breast milk and formula). Promptly identify and treat mastitis, thrush, and cracked or bleeding nipples, as these conditions may increase the risk of HIV transmission through breast-feeding. Breast-fed infants should undergo immediate diagnostic and virologic HIV testing. Testing should continue throughout breast-feeding and up to 6 months after cessation of breast-feeding. For expert consultation, healthcare workers may contact the Perinatal HIV Hotline (888-448-8765). Limited data suggest that low concentrations of raltegravir are transferred in human breast milk following maternal doses up to 1,200 mg daily; adverse effects are not expected in breast-fed infants. A small Swiss cohort found the median milk-to-plasma ratio was 0.96 for once daily dosing and 0.39 for twice daily dosing. Other antiretroviral medications whose passage into human breast milk have been evaluated include nevirapine, zidovudine, lamivudine, and nelfinavir.
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. The prevalence of transmitted drug resistance (TDR) in high-income countries ranges from 9% to 14% and varies by country. In most TDR surveys, non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance and nucleoside reverse transcriptase inhibitor (NRTI) resistance are the most common mutation class types detected, followed by protease inhibitor (PI) and integrase strand transfer inhibitor (INSTI) resistance mutations, respectively. Resistance testing at baseline can help optimize treatment and, thus, virologic response. In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but may still increase the risk of treatment failure when therapy is eventually initiated. Thus, if therapy is deferred, resistance testing should still be performed during acute HIV infection with the genotypic resistance test result kept in the patient's medical record until it becomes clinically useful. Additionally, because of the possibility of acquisition of another drug-resistant virus before treatment initiation, repeat resistance testing at the time therapy is initiated would be prudent.
Raltegravir is metabolized by the liver. Studies regarding the use of the 600 mg tablet formulation in patients with hepatic impairment have not been conducted; therefore, this formulation is not recommended for use in patients with any degree of hepatic impairment. For the other formulations, no dosage adjustment is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetic parameters has not been studied; caution is needed when administering raltegravir to patients with severe hepatic disease. Cautious administration is also recommended for patients with hepatitis. In general, the safety profile in subjects with hepatitis coinfection is similar to subjects without hepatitis. However, as compared with data from patients without hepatitis, a higher percentage of patients with chronic, active hepatitis 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. Patients presenting with HIV infection should be screened for hepatitis B virus (HBV) coinfection to assure appropriate treatment. Patients with hepatitis B and HIV coinfection should be started on a fully suppressive antiretroviral (ARV) therapy with activity against both viruses (regardless of CD4 counts and HBV DNA concentrations). HIV treatment guidelines recommend these patients receive an ARV regimen that contains a dual NRTI backbone of tenofovir alafenamide or tenofovir disoproxil fumarate with either emtricitabine or lamivudine. If tenofovir cannot be used, entecavir should be used in combination with a fully suppressive ARV regimen (note: entecavir should not be considered part of the ARV regimen). Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, tenofovir, or entecavir as the only active agent) as this may result in HIV resistant strains. Further, HBV treatment regimens that include adefovir or telbivudine should also be avoided, as these regimens are associated with a higher incidence of toxicities and increased rates of HBV treatment failure. Most patients with coinfection should continue treatment indefinitely with the goal of maximal HIV suppression and prevention of HBV relapse. If treatment must be discontinued, monitor transaminase concentrations every 6 weeks for the first 3 months, and every 3 to 6 months thereafter. For patients who refuse a fully suppressive ARV regimen, but still require treatment for HBV, consider 48 weeks of peginterferon alfa; do not administer HIV-active medications in the absence of a fully suppressive ARV regimen. Instruct patients with coinfection to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate.
Cautious administration is recommended for patients with hepatitis. In general, the safety profile in subjects with hepatitis coinfection is similar to subjects without hepatitis. However, as compared with data from patients without hepatitis, a higher percentage of patients with chronic, active hepatitis and baseline liver function tests not greater than 5-times the upper limit of normal had elevated AST, ALT, or total bilirubin. HIV treatment guidelines recommend all patients presenting with HIV infection undergo routine screening for hepatitis C virus (HCV). For HCV seronegative individuals who are at continued high risk of acquiring hepatitis C, specifically men who have sex with men (MSM) or persons who inject drugs, additional HCV screening is recommended annually or as indicated by clinical presentation (e.g., unexplained ALT elevation), risk activities, or exposure. Similarly, the AASLD/IDSA HCV guidelines and the CDC preexposure prophylaxis (PrEP) guidelines recommend HCV serologic testing at baseline and every 12 months for MSM, transgender women, and persons who inject drugs. Use an FDA-approved immunoassay licensed for detection of HCV antibodies (anti-HCV); in settings where acute HCV infection is suspected or in persons with known prior infection that cleared spontaneously or after treatment, use of nucleic acid testing for HCV RNA is recommended. If hepatitis C and HIV coinfection is identified, consider treating both viral infections concurrently. It is recommended to use a fully suppressive antiretroviral therapy and an HCV regimen in all patients with coinfection regardless of CD4 count, as lower CD4 counts do not appear to compromise the efficacy of HCV treatment. In most patients, a simplified pangenotypic HCV regimen (i.e., glecaprevir; pibrentasvir or sofosbuvir; velpatasvir) may be an appropriate choice; however, these regimens are NOT recommended for use in persons with HCV and HIV coinfection who: are treatment-experienced with HCV relapse (reinfection after successful therapy is not an exclusion); have decompensated cirrhosis; on a tenofovir disoproxil fumarate containing regimen with eGFR less than 60 mL/minute; on efavirenz, etravirine, nevirapine, or boosted protease inhibitor; have untreated chronic hepatitis B; are pregnant. Patients with HCV and HIV coinfection who meet these exclusion criteria should be treated for HCV following standard approaches as described in the AASLD/IDSA HCV guidelines. Treatment of HCV infection in children younger than 3 years is not usually recommended; however, treatment should be considered for all children 3 years and older with HCV and HIV coinfection who have no contraindications to treatment. Instruct patients with coinfection to avoid consuming alcohol, limit ingestion of potentially hepatotoxic medications, avoid iron supplementation in the absence of documented iron deficiency, and receive vaccinations against hepatitis A and hepatitis B as appropriate.
Antiretroviral therapy should be provided to all patients during pregnancy, regardless of HIV RNA concentrations or CD4 cell count. Using highly active antiretroviral combination therapy (HAART) to maximally suppress viral replication is the most effective strategy to prevent the development of resistance and to minimize the risk of perinatal transmission. Begin HAART as soon as pregnancy is recognized, or HIV is diagnosed. HIV guidelines recommend raltegravir, administered via twice-daily dosing, plus a 2-NRTI backbone as an alternative treatment option for use in pregnant patients and those trying to conceive. Available data from the Antiretroviral Pregnancy Registry (APR), which includes 570 first trimester exposures to raltegravir, have shown no difference in the risk of overall major birth defects when compared to the 2.7% background rate among pregnant women in the US. The prevalence of birth defects was 3.9% (95% CI: 2.4% to 5.8%) when exposure occurred in the first trimester. Regular laboratory monitoring is recommended to determine antiretroviral efficacy. Monitor CD4 counts at the initial visit. Patients who have been on HAART for at least 2 years and have consistent viral suppression and CD4 counts consistently greater than or equal to 300 cells/mm3 do not need CD4 counts monitored after the initial visit during the pregnancy. However, CD4 counts should be monitored every 3 months during pregnancy for patients on HAART less than 2 years and have CD4 counts less than 300 cells/mm3, patients with inconsistent adherence, or patients with detectable viral loads. For patients on HAART less than 2 years but have CD4 counts greater than or equal to 300 cells/mm3, monitor CD4 counts every 6 months. Monitor plasma HIV RNA at the initial visit (with review of prior levels), 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, and then at least every 3 months during pregnancy. Viral load should also be assessed at approximately 36 weeks gestation, or within 4 weeks of planned delivery, to inform decisions regarding mode of delivery and optimal treatment for newborns. Patients whose HIV RNA levels are above the threshold for resistance testing (usually greater than 500 copies/mL but may be possible for levels greater than 200 copies/mL in some laboratories) should undergo antiretroviral resistance testing (genotypic testing, and if indicated, phenotypic testing). Resistance testing should be conducted before starting therapy in treatment-naive patients who have not been previously tested, starting therapy in treatment-experienced patients (including those who have received pre-exposure prophylaxis), modifying therapy in patients who become pregnant while receiving treatment, or modifying therapy in patients who have suboptimal virologic response to treatment that was started during pregnancy. DO NOT delay initiation of antiretroviral therapy while waiting on the results of resistance testing; treatment regimens can be modified, if necessary, once the testing results are known. First trimester ultrasound is recommended to confirm gestational age and provide an accurate estimation of gestational age at delivery. A second trimester ultrasound can be used for both anatomical survey and determination of gestational age in those patients not seen until later in gestation. Perform standard glucose screening in patients receiving antiretroviral therapy at 24 to 28 weeks gestation, although it should be noted that some experts would perform earlier screening with ongoing chronic protease inhibitor-based therapy initiated prior to pregnancy, similar to recommendations for patients with high-risk factors for glucose intolerance. Liver function testing is recommended within 2 to 4 weeks after initiating or changing antiretroviral therapy, and approximately every 3 months thereafter during pregnancy (or as needed). All pregnant patients should be counseled about the importance of adherence to their antiretroviral regimen to reduce the potential for development of resistance and perinatal transmission. It is strongly recommended that antiretroviral therapy, once initiated, not be discontinued. If a patient decides to discontinue therapy, a consultation with an HIV specialist is recommended. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to raltegravir; information about the registry can be obtained at www.apregistry.com or by calling 1-800-258-4263.
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.
Clinical studies of raltegravir did not include sufficient numbers of patients aged 65 years or over to determine whether they respond differently from younger patients. In general, dose selection for a geriatric patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.
It may be prudent to use raltegravir with caution in patients with a history of psychiatric disease, including depression or suicidal ideation. Both depression and suicidal ideation and behaviors have been noted in post-marketing reports, particularly in patients with a preexisting history of psychiatric disease.
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of HIV treatment, patients whose immune system responds to raltegravir therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as progressive multifocal leukoencephalopathy (PML), mycobacterium avium complex (MAC), cytomegalovirus (CMV), Pneumocystis pneumonia (PCP), or tuberculosis (TB)), which may necessitate further evaluation and treatment. In addition, autoimmune disease (including Graves' disease, Guillain-Barre syndrome, and polymyositis) may also develop; the time to onset is variable and may occur months after treatment initiation.
Patients receiving raltegravir may be at increased risk of developing serious rash. According to the manufacturer, fatal skin reactions (e.g., Stevens-Johnson Syndrome, toxic epidermal necrolysis) have been reported during the post-marketing period. Cases of hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction have also been reported. Health care providers are advised to closely monitor the clinical status patients during treatment. Immediately discontinue raltegravir and initiate appropriate therapy in any patient who develops signs of severe skin reactions, such as severe rash or rash accompanied with fever, fatigue, general malaise, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, facial edema, angioedema, or eosinophilia. Failure to promptly discontinue raltegravir therapy may result in a life-threatening reaction.
Starting an integrase inhibitor-containing regimen (such as raltegravir) in treatment-naive patients has been associated with weight gain. Predictors and mechanisms for the increase in weight are still unclear; however, the weight gain appears to disproportionately affect females, Hispanic patients, and Black patients (particularly Black women). It is unknown whether the increase in weight is associated with significant cardio-metabolic risks or if it is reversible upon treatment discontinuation.
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 therapy for HIV treatment:
-For adults, initiation of treatment immediately (or as soon as possible) after HIV diagnosis is recommended in all patients to reduce the risk of disease progression and to prevent the transmission of HIV, including perinatal transmission and transmission to sexual partners. Starting antiretroviral therapy early is particularly important for patients with AIDS-defining conditions, those with acute or recent HIV infection, and individuals who are pregnant; delaying therapy in these subpopulations has been associated with high risks of morbidity, mortality, and HIV transmission.
-Prior to initiating treatment, obtain baseline plasma HIV RNA (viral load) and CD4 count; results do not need to be available before starting therapy.
-Antiretroviral drug-resistance testing:-Genotypic drug-resistance testing is recommended prior to initiation of therapy in all antiretroviral treatment-naive patients and prior to changing therapy for treatment failure.
--Standard genotypic drug-resistance testing in treatment-naive people should focus on testing for mutations in reverse transcriptase (RT) and protease (PR) genes.
-Testing for mutations in the integrase gene should also be performed if integrase strand transfer inhibitor (INSTI) resistance is a concern (e.g., people who acquire HIV after pre-exposure prophylaxis with long-acting cabotegravir).
-Phenotypic resistance testing may be used in conjunction with the genotypic test for patients with known or suspected complex drug-resistance mutation patterns.
-HIV-1 proviral DNA resistance testing is available for use in patients with HIV RNA concentrations below the limits of detection or with low-level viremia (i.e., less than 1,000 copies/mL), where genotypic testing is unlikely to be successful; however, the clinical utility of this assay has not been fully determined.
-It is not necessary to delay treatment until resistance test results are available; however, subsequent modifications to the treatment regimen should be made, if needed, once the test results are available.
-Pediatric guidelines are also available.
Place in therapy for HIV treatment:
-Raltegravir (twice daily) plus 2-NRTI is an alternative treatment option for most pregnant adults and adolescents with HIV-1, HIV-2, or HIV-1/HIV-2 coinfection; once daily raltegravir is NOT recommended for use during pregnancy.
-In certain clinical situations, raltegravir (once or twice daily) plus 2-NRTI is a preferred initial treatment regimen for some non-pregnant adults and adolescents with HIV-1, HIV-2, or HIV-1/HIV-2 coinfection
-In non-pregnant patients unable to take abacavir or tenofovir, raltegravir (twice daily) may be given in combination with darunavir boosted with ritonavir if HIV RNA is less than 100,000 copies/mL, CD4 is more than 200 cells/mm3, and without HBV coinfection.
-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).
-Pediatric guidelines are also available.
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 (400 mg film-coated tablet):
NOTE: Due to differences in exposure observed between the formulations in clinical trials, the 400 mg film-coated tablet is the preferred formulation in pediatric patients weighing 25 kg or more; however, the chewable tablet may be used in patients who are unable to swallow the film-coated tablet. There are no data in pediatrics to guide dosage during coadministration with rifampin.
Adults: 400 mg PO twice daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children and Adolescents weighing 25 kg or more: 400 mg PO twice daily.
Oral dosage (600 mg film-coated tablet):
Adults: 1,200 mg PO once daily. The high dose regimen is indicated for treatment-naive patients or patients who are virologically suppressed on an initial regimen of 400 mg twice daily. Coadministration with rifampin is not recommended.
Children and Adolescents weighing 40 kg or more: 1,200 mg PO once daily. The high dose (HD) regimen is indicated for treatment-naive patients or patients who are virologically suppressed on an initial regimen of 400 mg twice daily. Coadministration with rifampin is not recommended. 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.
Oral dosage (chewable tablets):
NOTE: Due to differences in exposure observed between the formulations in clinical trials, the 400 mg film-coated tablet is the preferred formulation in pediatric patients weighing 25 kg or more; however, the chewable tablet may be used in patients who are unable to swallow the film-coated tablet. There are no data in pediatrics to guide dosage during coadministration with rifampin.
Children and Adolescents weighing 40 kg or more: 300 mg PO twice daily.
Children and Adolescents weighing 28 to 39 kg: 200 mg PO twice daily.
Children weighing 20 to 27 kg: 150 mg PO twice daily.
Children weighing 14 to 19 kg: 100 mg PO twice daily.
Children weighing 11 to 13 kg: 75 mg PO twice daily.
Oral dosage (powder for suspension):
NOTE: There are no data in pediatrics to guide dosage during coadministration with rifampin.
Children weighing 14 to 19 kg: 100 mg PO twice daily.
Infants and Children 4 weeks and older weighing 11 to 13 kg: 80 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 6 to 7 kg: 40 mg PO twice daily.
Infants 4 weeks and older weighing 4 to 5 kg: 30 mg PO twice daily.
Infants 4 weeks and older weighing 3 kg: 25 mg PO twice daily.
Term Neonates older than 7 days weighing 4 kg: 15 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 2 kg: 8 mg PO twice daily (approximately 3 mg/kg/dose).
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 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 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.
For human immunodeficiency virus (HIV) prophylaxis*:
-for human immunodeficiency virus (HIV) prophylaxis* after occupational exposure:
Oral dosage (film-coated tablets):
Adults: 400 mg PO twice daily in combination with tenofovir and either emtricitabine or lamivudine for 28 days are preferred HIV post-exposure prophylaxis (PEP) regimens. A 3-drug regimen is recommended; however, the use of a 2-drug regimen would be preferred to discontinuing prophylaxis completely if tolerability is a concern. Begin prophylaxis as soon as possible, ideally within 2 hours of exposure. If initiation of prophylaxis is delayed (beyond 36 hours or 72 hours after exposure), efficacy of the antiretroviral regimen may be diminished and treatment should be determined on a case-by-case basis. Exposures for which PEP is indicated include: skin puncture by a sharp object that has been contaminated with blood, body fluid, or other infectious material; bite from a patient with visible bleeding in the mouth which causes bleeding by the exposed worker; splash of blood, body fluid, or other infectious material onto the workers mouth, nose, or eyes; exposure of blood, body fluid, or other infectious material on a workers non-intact skin (i.e., open wound, chapped skin, abrasion, dermatitis).
-for human immunodeficiency virus (HIV) prophylaxis* after nonoccupational exposure, including sexual assault:
NOTE: Higher risk exposures for which prophylaxis is recommended include exposure of vagina, rectum, eye, mouth, or other mucous membrane, nonintact skin, or percutaneous contact with blood, semen, vaginal secretions, rectal secretions, breast milk, or any body fluid that is visibly contaminated with blood when the source is known to be HIV-positive. Exposures to a source patient with unknown HIV status should be assessed on a case-by-case basis.
Oral dosage (film-coated tablets):
Adults: 400 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is a preferred HIV post-exposure prophylaxis (PEP) regimen in adults. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Children and Adolescents weighing 25 kg or more: 400 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is a preferred HIV post-exposure prophylaxis (PEP) regimen in children and adolescents weighing 25 kg or more. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Oral dosage (chewable tablets):
Children 2 to 12 years weighing 40 kg or more: 300 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is a preferred HIV post-exposure prophylaxis (PEP) regimen in children 2 years and older. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Children 2 to 12 years weighing 28 to 39 kg: 200 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is a preferred HIV post-exposure prophylaxis (PEP) regimen in children 2 years and older. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Children 2 to 12 years weighing 20 to 27 kg: 150 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is a preferred HIV post-exposure prophylaxis (PEP) regimen in children 2 years and older. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Children 2 to 12 years weighing 14 to 19 kg: 100 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is a preferred HIV post-exposure prophylaxis (PEP) regimen in children 2 years and older. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Children 2 to 12 years weighing 11 to 13 kg: 75 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is a preferred HIV post-exposure prophylaxis (PEP) regimen in children 2 years and older. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
For perinatal human immunodeficiency virus (HIV) prophylaxis* in neonates at high risk for HIV acquisition:
NOTE: Presumptive therapy with a 3-drug combination antiretroviral (ARV) regimen, consisting of zidovudine, lamivudine, and 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):
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.
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 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.
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.
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 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 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 dose 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 dose 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 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 dose 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.
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 patients. However, therapeutic drug monitoring may be considered in the following situations :-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
-pregnant patients who have risk factors for virologic failure, particularly during the later stages of pregnancy
-use of drugs in children with limited pharmacokinetic data and/or therapeutic experience
Maximum Dosage Limits:
-Adults
800 mg/day PO for the 400 mg film-coated tablet; 1,600 mg/day PO with concomitant rifampin; 1,200 mg/day for the 600 mg film-coated tablet; safety and efficacy of other formulations have not been established.
-Geriatric
800 mg/day PO for the 400 mg film-coated tablet; 1,600 mg/day PO with concomitant rifampin; 1,200 mg/day for the 600 mg film-coated tablet; safety and efficacy of other formulations have not been established.
-Adolescents
weight 40 kg or more: 600 mg/day PO for the chewable tablet; 800 mg/day PO for the 400 mg film-coated tablet; 1,200 mg/day for the 600 mg film-coated tablet; safety and efficacy have not been established for the oral suspension.
weight 28 to 39 kg: 400 mg/day PO for the chewable tablet; 800 mg/day PO for the 400 mg film-coated tablet; safety and efficacy of other formulations have not been established.
-Children
weight 40 kg or more: 600 mg/day PO for the chewable tablet; 800 mg/day PO for the 400 mg film-coated tablet; 1,200 mg/day for the 600 mg film-coated tablet; safety and efficacy have not been established for the oral suspension.
weight 28 to 39 kg: 400 mg/day PO for the chewable tablet; 800 mg/day PO for the 400 mg film-coated tablet; safety and efficacy of other formulations have not been established.
weight 25 to 27 kg: 300 mg/day PO for the chewable tablet; 800 mg/day PO for the 400 mg film-coated tablet; safety and efficacy of other formulations have not been established.
weight 20 to 24 kg: 300 mg/day PO for the chewable tablet; safety and efficacy of other formulations have not been established.
weight 14 to 19 kg: 200 mg/day PO for the oral suspension or chewable tablet; safety and efficacy have not been established for the film-coated tablets.
weight 11 to 13 kg: 160 mg/day PO for the oral suspension; 150 mg/day PO for the chewable tablet; safety and efficacy have not been established for the film-coated tablets.
weight 8 to 10 kg: 120 mg/day PO for the oral suspension; safety and efficacy of other formulations have not been established.
-Infants
weight 11 to 13 kg: 160 mg/day PO for the oral suspension; 150 mg/day PO for the chewable tablet; safety and efficacy have not been established for the film-coated tablets.
weight 8 to 10 kg: 120 mg/day PO for the oral suspension; safety and efficacy of other formulations have not been established.
weight 6 to 7 kg: 80 mg/day PO for the oral suspension; safety and efficacy of other formulations have not been established.
weight 4 to 5 kg: 60 mg/day PO for the oral suspension; safety and efficacy of other formulations have not been established.
weight 3 kg: 50 mg/day PO for the oral suspension; safety and efficacy of other formulations have not been established.
-Neonates
Term Neonates 8 days and older weighing 4 kg: 30 mg/day PO for the oral suspension; safety and efficacy of other formulations have not been established.
Term Neonates 8 days and older weighing 3 kg: 20 mg/day PO for the oral suspension; safety and efficacy of other formulations have not been established.
Term Neonates 8 days and older weighing 2 kg: 16 mg/day PO for the oral suspension; safety and efficacy of other formulations have not been established.
Term Neonates 0 to 7 days weighing 4 kg: 7 mg/day PO for the oral suspension; safety and efficacy of other formulations have not been established.
Term Neonates 0 to 7 days weighing 3 kg: 5 mg/day PO for the oral suspension; safety and efficacy of other formulations have not been established.
Term Neonates 0 to 7 days weighing 2 kg: 4 mg/day PO for the oral suspension; safety and efficacy of other formulations have not been established.
Premature and Term Neonates weighing less than 2 kg: Safety and efficacy have not been established.
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
Aluminum Hydroxide: (Major) Coadministration or staggered administration of aluminum and/or magnesium-containing antacids is not recommended during treatment with raltegravir. Coadministration may result in decreased plasma concentrations of raltegravir, which may lead to HIV treatment failure or the development of viral resistance. In a drug interaction study, the AUC for raltegravir was decreased by 49% (90% CI, 35% to 60%), 51% (90% CI, 33% to 65%), and 30% (90% CI, 4% to 50%), when administered with, 2 hours before, and 2 hours after aluminum/magnesium hydroxide antacids, respectively.
Aluminum Hydroxide; Magnesium Carbonate: (Major) Coadministration or staggered administration of aluminum and/or magnesium-containing antacids is not recommended during treatment with raltegravir. Coadministration may result in decreased plasma concentrations of raltegravir, which may lead to HIV treatment failure or the development of viral resistance. In a drug interaction study, the AUC for raltegravir was decreased by 49% (90% CI, 35% to 60%), 51% (90% CI, 33% to 65%), and 30% (90% CI, 4% to 50%), when administered with, 2 hours before, and 2 hours after aluminum/magnesium hydroxide antacids, respectively.
Aluminum Hydroxide; Magnesium Hydroxide: (Major) Coadministration or staggered administration of aluminum and/or magnesium-containing antacids is not recommended during treatment with raltegravir. Coadministration may result in decreased plasma concentrations of raltegravir, which may lead to HIV treatment failure or the development of viral resistance. In a drug interaction study, the AUC for raltegravir was decreased by 49% (90% CI, 35% to 60%), 51% (90% CI, 33% to 65%), and 30% (90% CI, 4% to 50%), when administered with, 2 hours before, and 2 hours after aluminum/magnesium hydroxide antacids, respectively.
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Major) Coadministration or staggered administration of aluminum and/or magnesium-containing antacids is not recommended during treatment with raltegravir. Coadministration may result in decreased plasma concentrations of raltegravir, which may lead to HIV treatment failure or the development of viral resistance. In a drug interaction study, the AUC for raltegravir was decreased by 49% (90% CI, 35% to 60%), 51% (90% CI, 33% to 65%), and 30% (90% CI, 4% to 50%), when administered with, 2 hours before, and 2 hours after aluminum/magnesium hydroxide antacids, respectively.
Aluminum Hydroxide; Magnesium Trisilicate: (Major) Coadministration or staggered administration of aluminum and/or magnesium-containing antacids is not recommended during treatment with raltegravir. Coadministration may result in decreased plasma concentrations of raltegravir, which may lead to HIV treatment failure or the development of viral resistance. In a drug interaction study, the AUC for raltegravir was decreased by 49% (90% CI, 35% to 60%), 51% (90% CI, 33% to 65%), and 30% (90% CI, 4% to 50%), when administered with, 2 hours before, and 2 hours after aluminum/magnesium hydroxide antacids, respectively.
Amlodipine; Atorvastatin: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
Antacids: (Major) Coadministration or staggered administration of aluminum and/or magnesium-containing antacids is not recommended during treatment with raltegravir. Coadministration may result in decreased plasma concentrations of raltegravir, which may lead to HIV treatment failure or the development of viral resistance. In a drug interaction study, the AUC for raltegravir was decreased by 49% (90% CI, 35% to 60%), 51% (90% CI, 33% to 65%), and 30% (90% CI, 4% to 50%), when administered with, 2 hours before, and 2 hours after aluminum/magnesium hydroxide antacids, respectively.
Atorvastatin: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
Calcium Carbonate: (Major) Coadministration of calcium carbonate with raltegravir administered as a once daily dose (high dose regimen) is not recommended. Coadministration may result in decreased plasma concentrations of raltegravir, which may lead to HIV treatment failure or the development of viral resistance. Calcium carbonate may be given with other dosage regimens of raltegravir with no dose adjustments necessary. In a drug interaction study (n = 19), the AUC of raltegravir, given as a single 1200 mg dose, was decreased by 72% (90% CI, 68% to 76%) when administered with a calcium carbonate antacid.
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Major) Coadministration of calcium carbonate with raltegravir administered as a once daily dose (high dose regimen) is not recommended. Coadministration may result in decreased plasma concentrations of raltegravir, which may lead to HIV treatment failure or the development of viral resistance. Calcium carbonate may be given with other dosage regimens of raltegravir with no dose adjustments necessary. In a drug interaction study (n = 19), the AUC of raltegravir, given as a single 1200 mg dose, was decreased by 72% (90% CI, 68% to 76%) when administered with a calcium carbonate antacid.
Calcium Carbonate; Magnesium Hydroxide: (Major) Coadministration of calcium carbonate with raltegravir administered as a once daily dose (high dose regimen) is not recommended. Coadministration may result in decreased plasma concentrations of raltegravir, which may lead to HIV treatment failure or the development of viral resistance. Calcium carbonate may be given with other dosage regimens of raltegravir with no dose adjustments necessary. In a drug interaction study (n = 19), the AUC of raltegravir, given as a single 1200 mg dose, was decreased by 72% (90% CI, 68% to 76%) when administered with a calcium carbonate antacid.
Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Major) Coadministration of calcium carbonate with raltegravir administered as a once daily dose (high dose regimen) is not recommended. Coadministration may result in decreased plasma concentrations of raltegravir, which may lead to HIV treatment failure or the development of viral resistance. Calcium carbonate may be given with other dosage regimens of raltegravir with no dose adjustments necessary. In a drug interaction study (n = 19), the AUC of raltegravir, given as a single 1200 mg dose, was decreased by 72% (90% CI, 68% to 76%) when administered with a calcium carbonate antacid.
Calcium Carbonate; Simethicone: (Major) Coadministration of calcium carbonate with raltegravir administered as a once daily dose (high dose regimen) is not recommended. Coadministration may result in decreased plasma concentrations of raltegravir, which may lead to HIV treatment failure or the development of viral resistance. Calcium carbonate may be given with other dosage regimens of raltegravir with no dose adjustments necessary. In a drug interaction study (n = 19), the AUC of raltegravir, given as a single 1200 mg dose, was decreased by 72% (90% CI, 68% to 76%) when administered with a calcium carbonate antacid.
Calcium; Vitamin D: (Major) Coadministration of calcium carbonate with raltegravir administered as a once daily dose (high dose regimen) is not recommended. Coadministration may result in decreased plasma concentrations of raltegravir, which may lead to HIV treatment failure or the development of viral resistance. Calcium carbonate may be given with other dosage regimens of raltegravir with no dose adjustments necessary. In a drug interaction study (n = 19), the AUC of raltegravir, given as a single 1200 mg dose, was decreased by 72% (90% CI, 68% to 76%) when administered with a calcium carbonate antacid.
Carbamazepine: (Major) Coadministration of carbamazepine with raltegravir is not recommended. Raltegravir is a substrate of uridine diphosphate glucuronosyltransferase (UGT) 1A1; carbamazepine is a strong UGT1A1 inducer. Although not specifically studied with carbamazepine, other strong UGT1A1 inducers have been shown to decrease plasma concentrations of raltegravir, which may lead to HIV treatment failure or to the development of viral resistance.
Etravirine: (Major) Coadministration of etravirine with raltegravir administered as a once daily dose (high dose regimen) is not recommended. Raltegravir is a substrate of uridine diphosphate glucuronosyltransferase (UGT) 1A; etravirine is a UGT1A1 inducer. Coadministration may result in decreased raltegravir concentrations, although the effects of etravirine on the pharmacokinetics of raltegravir administered once daily have not been studied. Etravirine may be given with other dosage regimens of raltegravir with no dose adjustments necessary. In drug interaction studies, etravirine had no clinically meaningful effect on the pharmacokinetics of raltegravir 400 mg twice daily.
Ezetimibe; Simvastatin: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
Fenofibrate: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as fibric acid derivatives.
Fenofibric Acid: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as fibric acid derivatives.
Fibric acid derivatives: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as fibric acid derivatives.
Fluvastatin: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
Fosamprenavir: (Moderate) Coadministration of fosamprenavir with raltegravir may alter the serum concentrations of both medications. According to the manufacturer, the appropriate dose adjustments for coadministration have not been established. During clinical studies, ampenavir pharmacokinetic parameters were altered when various fosamprenavir doses (i.e., 700 mg BID, 1400 mg BID, 1400 mg daily) were administered concurrently with raltegravir 400 mg PO twice daily. The recorded amprenavir pharmacokinetic parameters ranged from a Cmax reduction of 27% to an increase of 27%, an AUC reduction of 36% to an increase of 13%, and a Cmin reduction of 17% to 50%.
Fosphenytoin: (Major) Coadministration of fosphenytoin with raltegravir is not recommended. Raltegravir is a substrate of uridine diphosphate glucuronosyltransferase (UGT) 1A1; fosphenytoin is a strong UGT1A1 inducer. Although not specifically studied with fosphenytoin, other strong UGT1A1 inducers have been shown to decrease plasma concentrations of raltegravir, which may lead to HIV treatment failure or to the development of viral resistance.
Gemfibrozil: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as fibric acid derivatives.
HMG-CoA reductase inhibitors: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Coadministration of rifampin with raltegravir administered as a once daily dose (high dose regimen) is not recommended. Increase the raltegravir dose to 800 mg PO twice daily when administered as the twice daily regimen in adults. Concurrent use of raltegravir with rifampin has not been studied in pediatric patients. Raltegravir is a substrate of uridine diphosphate glucuronosyltransferase (UGT) 1A1; rifampin is a strong UGT1A1 inducer. Coadministration may result in decreased plasma raltegravir concentrations, which could lead to HIV treatment failure or to the development of viral resistance. In a drug interaction study, the AUC for raltegravir 400 mg was reduced by 40% when coadministered with rifampin. The effects of rifampin on the pharmacokinetics of raltegravir administered once daily are not known.
Isoniazid, INH; Rifampin: (Major) Coadministration of rifampin with raltegravir administered as a once daily dose (high dose regimen) is not recommended. Increase the raltegravir dose to 800 mg PO twice daily when administered as the twice daily regimen in adults. Concurrent use of raltegravir with rifampin has not been studied in pediatric patients. Raltegravir is a substrate of uridine diphosphate glucuronosyltransferase (UGT) 1A1; rifampin is a strong UGT1A1 inducer. Coadministration may result in decreased plasma raltegravir concentrations, which could lead to HIV treatment failure or to the development of viral resistance. In a drug interaction study, the AUC for raltegravir 400 mg was reduced by 40% when coadministered with rifampin. The effects of rifampin on the pharmacokinetics of raltegravir administered once daily are not known.
Lovastatin: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
Magnesium Hydroxide: (Major) Coadministration or staggered administration of aluminum and/or magnesium-containing antacids is not recommended during treatment with raltegravir. Coadministration may result in decreased plasma concentrations of raltegravir, which may lead to HIV treatment failure or the development of viral resistance. In a drug interaction study, the AUC for raltegravir was decreased by 49% (90% CI, 35% to 60%), 51% (90% CI, 33% to 65%), and 30% (90% CI, 4% to 50%), when administered with, 2 hours before, and 2 hours after aluminum/magnesium hydroxide antacids, respectively.
Phenobarbital: (Major) Coadministration of phenobarbital with raltegravir is not recommended. Raltegravir is a substrate of uridine diphosphate glucuronosyltransferase (UGT) 1A1; phenobarbital is a strong UGT1A1 inducer. Although not specifically studied with phenobarbital, other strong UGT1A1 inducers have been shown to decrease plasma concentrations of raltegravir, which may lead to HIV treatment failure or to the development of viral resistance.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Coadministration of phenobarbital with raltegravir is not recommended. Raltegravir is a substrate of uridine diphosphate glucuronosyltransferase (UGT) 1A1; phenobarbital is a strong UGT1A1 inducer. Although not specifically studied with phenobarbital, other strong UGT1A1 inducers have been shown to decrease plasma concentrations of raltegravir, which may lead to HIV treatment failure or to the development of viral resistance.
Phenytoin: (Major) Coadministration of phenytoin with raltegravir is not recommended. Raltegravir is a substrate of uridine diphosphate glucuronosyltransferase (UGT) 1A1; phenytoin is a strong UGT1A1 inducer. Although not specifically studied with phenytoin, other strong UGT1A1 inducers have been shown to decrease plasma concentrations of raltegravir, which may lead to HIV treatment failure or to the development of viral resistance.
Pitavastatin: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
Pravastatin: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
Primidone: (Major) Coadministration of primidone with raltegravir is not recommended. Raltegravir is a substrate of uridine diphosphate glucuronosyltransferase (UGT) 1A1; phenobarbital, the active metabolite of primidone, is a strong UGT1A1 inducer. Although not specifically studied with phenobarbital, other strong UGT1A1 inducers have been shown to decrease plasma concentrations of raltegravir, which may lead to HIV treatment failure or to the development of viral resistance.
Rifampin: (Major) Coadministration of rifampin with raltegravir administered as a once daily dose (high dose regimen) is not recommended. Increase the raltegravir dose to 800 mg PO twice daily when administered as the twice daily regimen in adults. Concurrent use of raltegravir with rifampin has not been studied in pediatric patients. Raltegravir is a substrate of uridine diphosphate glucuronosyltransferase (UGT) 1A1; rifampin is a strong UGT1A1 inducer. Coadministration may result in decreased plasma raltegravir concentrations, which could lead to HIV treatment failure or to the development of viral resistance. In a drug interaction study, the AUC for raltegravir 400 mg was reduced by 40% when coadministered with rifampin. The effects of rifampin on the pharmacokinetics of raltegravir administered once daily are not known.
Rosuvastatin: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
Rosuvastatin; Ezetimibe: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
Simvastatin: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
Tipranavir: (Major) Coadministration of tipranavir plus ritonavir with raltegravir administered as a once daily dose (high dose regimen) is not recommended, as concurrent use results in decreased raltegravir concentrations. Tipranavir/ritonavir may be given with other dosage regimens of raltegravir with no dose adjustments necessary. Raltegravir is a substrate of uridine diphosphate glucuronosyltransferase (UGT) 1A1; tipranavir given with ritonavir is a UGT1A1 inducer. In drug interaction studies, tipranavir; ritonavir had no clinically meaningful effect on the pharmacokinetics of raltegravir 400 mg twice daily.
Raltegravir inhibits the catalytic activity of HIV integrase, which is an HIV encoded enzyme required for viral replication. Integrase is 1 of the 3 HIV-1 enzymes required for viral replication. Integration of HIV into cellular DNA is a multi-step process. First, the assembly of integrase in a stable complex with the viral DNA occurs. Second, the terminal dinucleotide from each 39 end of the viral DNA is removed by endonucleolytic processing. Lastly, the viral DNA 3' ends are covalently linked to the cellular (target) DNA by strand transfer. The last 2 processes, which are catalytic, require integrase to be appropriately assembled on a specific viral DNA substrate. Inhibition of integrase by raltegravir prevents the covalent insertion, or integration, of unintegrated linear HIV DNA into the host cell genome preventing the formation of the HIV provirus. The provirus is required to direct the production of progeny virus, so inhibiting integration prevents propagation of the viral infection. Raltegravir did not significantly inhibit human phosphoryl transferases including DNA polymerases alpha, beta, and gamma.
No dose-response effect occurred over the dose range of 200 to 600 mg orally twice daily. After 24 weeks of raltegravir plus optimized background therapy, the mean viral load reduction from baseline was 1.8 log10 copies/mL for raltegravir 200 mg twice daily, 1.87 log10 copies/mL for 400 mg twice daily, and 1.84 log10 copies/ml for 600 mg twice daily. A similar percentage of patients had a HIV-1 RNA of less than 400 copies/mL: 69.8% of the 200 mg group, 71.1% of the 400 mg group, and 71.1% of the 600 mg group. Of note, 72% of the study population's viral isolate was not sensitive to any antiretroviral in their optimized background regimen.
Twice daily administration led to a mean concentration of 70.6 nM 12 hours after a 100 mg dose. The geometric mean concentration was 107.1 nM after dosing with 200 mg and 200.6 nM after dosing with 400 mg. Raltegravir at concentrations of 31 +/- 20 nM resulted in 95% inhibition (EC95) of viral spread relative to an untreated virus-infected culture in human T-lymphoid cell cultures infected with the cell-line adapted HIV-1 variant H9IIIB. In addition, concentrations of 6 to 50 nM resulted in 95% inhibition of viral spread in cultures of mitogen-activated human peripheral blood mononuclear cells infected with diverse, primary clinical isolates of HIV-1, including isolates resistant to reverse transcriptase inhibitors and protease inhibitors. Raltegravir also inhibited replication of an HIV-2 isolate when tested in CEMx174 cells (EC95 of 6 nM). Additive to synergistic antiretroviral activity was observed when human T-lymphoid cells infected with the H9IIIB variant of HIV-1 were incubated with raltegravir and delavirdine, efavirenz, nevirapine, abacavir, didanosine, lamivudine, stavudine, tenofovir, zalcitabine, zidovudine, amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or enfuvirtide.
Among 160 treatment-naive patients who got raltegravir, lamivudine, and tenofovir for 48 weeks, 5 had virologic failure. The N155H amino acid substitution in the integrase region was noted in 2 patients; the substitution was not present before treatment. Two other patients had resistance-conferring mutations detected in the reverse transcriptase region only. The last patient had virus with no known resistance mutations. Mutations observed in the HIV-1 integrase coding sequence that contributed to raltegravir resistance generally included an amino acid substitution at either Y143, Q148, or N155 plus one or more additional substitutions.
Cross-resistance with other HIV-1 integrase strand transfer inhibitors (ISTIs) has been identified; generally, mutations conferring resistance to raltegravir also confer resistance to elvitegravir. Specific amino acid substitutions resulting in reduced susceptibility to the ISTI class include Y143, E92Q, and Q148 plus.
Raltegravir is administered orally. It is approximately 83% bound to human plasma protein over the concentration range of 2 to 10 micromole. It distributes into the cerebrospinal fluid (CSF) at a proportion 3-fold lower than the free fraction in plasma, with median CSF concentration being 5.8% (range: 1% to 53.5%) of the corresponding plasma concentration. Elimination is mainly by metabolism via a UDP-glucuronosyltransferases 1A1 (UGT1A1)-mediated glucuronidation pathway. Data are not sufficient to determine the impact of UGT1A1 polymorphism on pharmacokinetic parameter values. The apparent terminal half-life is approximately 9 hours. Approximately 51% of an oral, radiolabeled dose was excreted in the feces, and 32% was excreted in urine. In feces, only raltegravir was present. Most of the drug in the feces is likely derived from hydrolysis of raltegravir-glucuronide secreted in bile. In urine, both raltegravir (9%) and raltegravir-glucuronide (23%) were detected. The major circulating entity was raltegravir and represented approximately 70% of the total radioactivity; the remaining radioactivity in plasma was accounted for by raltegravir-glucuronide.
Affected cytochrome P450 isoenzymes: none
In vitro, raltegravir does not induce cytochrome P450 (CYP) 3A4, CYP1A2, or CYP2B6, nor does it inhibit UGT1A1, UGT2B7, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A. It does not inhibit P-glycoprotein (P-gp)-mediated transport. Raltegravir is not a substrate of CYP enzymes.
-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
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.
Pediatrics
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 59 pediatric patients with HIV (ages 4 weeks to 18 years) 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)
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
Other
Pregnancy
Twice daily dosing is required during pregnancy. Two studies have evaluated the effects of pregnancy on the pharmacokinetic of raltegravir 400 mg twice daily. In the first study, plasma drug exposures (AUC) and trough concentrations (Cmin) observed during the third trimester were similar to those obtained during postpartum. In addition, the third trimester Cmin values for all 10 study patients were above the therapeutic target concentration. The other study, involving 22 pregnant women, observed a 29% decrease in raltegravir AUC (90% CI: 0.53, 0.96) and a 36% decrease in Cmin concentrations (90% CI: 0.34, 1.22) in the third trimester as compared with postpartum. Despite these varying results, antepartum values in both studies were similar to historical data for non-pregnant adults. For raltegravir 1,200 mg once daily, a population pharmacokinetic model pooled 11 pharmacokinetic studies (n = 221) with primary target for efficacy set as the lower bound of the 90% confidence interval of the trough concentration greater than 0.75. The simulated trough geometric mean ratio (GMR) for raltegravir 1,200 mg once daily was 0.51 (CI: 0.41, 0.63), falling below the primary target for efficacy; thereby, supporting the current recommendation against daily raltegravir dosing in pregnancy. Raltegravir has high placental transfer to the fetus.
Pharmacogenomics
In the neonatal study, IMPAACT P1110, there was no association between apparent clearance of raltegravir and UGT1A1 genotype polymorphisms.