Integrase Inhibitors
Raltegravir
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Tablet: 400 mg (film-coated poloxamer tablet) High-Dose (HD) Tablet: 600 mg (film-coated poloxamer tablet) Chewable Tablets: 100 mg (scored) and 25 mg Granules for Oral Suspension: Single-use packet of 100 mg of raltegravir, suspended in 10 mL of water for a final concentration of 10 mg/mL Film-coated tablets, chewable tablets, and oral suspension are not interchangeable. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dosing Recommendations | Selected Adverse Events | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Note: No dosing information is available for preterm infants or infants weighing <2 kg at birth. See Table 13 in Antiretroviral Management of Newborns with Perinatal HIV Exposure or HIV Infection for information about using raltegravir (RAL) for the prevention of perinatal HIV transmission. Neonate (Weighing ≥2 kg) Dosea, b RAL Oral Suspension Dosing Table for Full-Term Neonates from Birth to Age 4 Weeks Neonates Aged ≥37 Weeks and Weighing ≥2 kg
Note: If the mother has taken RAL 2–24 hours prior to delivery, the neonate’s first dose should be delayed until 24–48 hours after birth. Infant >4 Weeks of Age and Child (Weighing ≥3 kg to <20 kg) Dose
RAL Oral Suspension Dosing Table for Patients Aged >4 Weeksa Note: The maximum dose of oral suspension is 10 mL (RAL 100 mg) twice daily.
Child and Adolescent Dose for Chewable Tablets, Film-Coated Tablets, and HD Tablets Children Weighing ≥3 kg
Children and Adolescents Weighing ≥40 kg
Chewable Tablet Dosing Tablea Note: The maximum dose of chewable tablets is RAL 300 mg twice daily.
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Special Instructions | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Metabolism/Elimination | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Raltegravir Dosing in Patients with Hepatic Impairment
Raltegravir Dosing in Patients with Renal Impairment
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Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent Antiretroviral Guidelines and the HIV Drug Interaction Checker.
- Metabolism: The major route of raltegravir (RAL) elimination is mediated through glucuronidation by uridine diphosphate glucuronyl transferase (UGT) 1A1.
- Coadministering RAL with inducers of UGT1A1—such as rifampin and tipranavir—may result in reduced plasma concentrations of RAL. Inhibitors of UGT1A1—such as atazanavir (ATV)— may increase plasma concentrations of RAL. No dosing modifications are recommended when RAL is coadministered with atazanavir/ritonavir (ATV/r) or tipranavir/ritonavir (TPV/r). However, RAL high-dose (HD) tablets should not be coadministered with TPV/r.
- In adults, an increased dose of RAL is recommended when it is coadministered with rifampin. For adults receiving rifampin, the recommended RAL dose is 800 mg twice daily. Do not coadminister rifampin with once-daily RAL HD tablets. In children aged 4 weeks to <12 years who had tuberculosis (TB)/HIV coinfection and were taking rifampin, RAL 12 mg/kg per dose twice daily of the chewable tablet formulation safely achieved pharmacokinetic (PK) targets.2,3 In a single case report of a 6-month-old infant receiving RAL oral granules for suspension and rifampicin for TB prophylaxis, 3 to 4 times the currently recommended dose of 12 mg/kg twice daily was needed4 to achieve target trough concentrations (Ctrough) >0.022 mg/L.
- Aluminum-containing antacids and magnesium-containing antacids may reduce RAL plasma concentrations and should not be coadministered with RAL.
- Significant drug interactions may be more likely to occur with RAL HD once daily. Trough concentration (Ctrough) in adults is approximately 30% lower with RAL HD 1,200 mg once daily than with RAL 400 mg twice daily. A lower Ctrough increases the potential for clinically significant drug interactions with interfering drugs that decrease RAL exposure and further lower Ctrough. In addition to aluminum-containing and magnesium-containing antacids, the following drugs should not be coadministered with the RAL HD formulation: calcium carbonate antacids, rifampin, TPV/r, and etravirine. The impact of other strong inducers of drug-metabolizing enzymes on RAL is unknown; coadministration with phenytoin, phenobarbital, and carbamazepine is not recommended.
- Before administering RAL, clinicians should carefully review a patient’s medication profile for potential drug interactions with RAL.
Major Toxicities
- More common: Nausea, headache, dizziness, diarrhea, fatigue, itching, insomnia.
- Less common: Abdominal pain, vomiting. Patients with chronic active hepatitis B virus infection and/or hepatitis C virus infection are more likely to experience a worsening adverse events (AEs) grade from baseline for laboratory abnormalities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin than patients who are not coinfected.
- Rare: Moderate-to-severe increase in creatine phosphokinase levels. Use RAL with caution in patients who are receiving medications that are associated with myopathy and rhabdomyolysis. Anxiety, depression, and paranoia, especially in those with a history of these conditions. Rash (including Stevens-Johnson syndrome), hypersensitivity reaction, DRESS (drug reaction with eosinophilia and systemic symptoms),5,6 and toxic epidermal necrolysis. Thrombocytopenia. Cerebellar ataxia. Hepatic failure (with and without associated hypersensitivity) in patients with underlying liver disease and/or concomitant medications.
Resistance
The International AIDS Society–USA maintains a list of updated resistance mutations, and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation.
Pediatric Use
Approval
RAL is an integrase strand transfer inhibitor that is approved by the U.S. Food and Drug Administration (FDA) for use in combination with other antiretroviral (ARV) drugs for the treatment of HIV in pediatric patients weighing ≥2 kg. The current pediatric FDA approval and dose recommendations are based on evaluations of 122 patients aged ≥4 weeks to 18 years who participated in IMPAACT P1066 and 42 full-term neonates who were treated for ≤6 weeks starting from birth and followed for a total of 24 weeks during IMPAACT P1110.7
The FDA has approved RAL HD, which allows once-daily dosing, for use in children and adolescents weighing ≥40 kg.
Efficacy in Clinical Trials
RAL has been evaluated in adults in three large, randomized clinical trials: STARTMRK, SPRING‑2, and ACTG A5257. STARTMRK compared the safety and efficacy of a RAL-containing regimen and an efavirenz (EFV)-containing regimen. At 48 weeks, RAL was noninferior to EFV. However, more patients discontinued EFV during the longer follow-up periods of 4 and 5 years, and RAL was found to be virologically and immunologically superior to EFV.8-10 Results from the SPRING-2 study in treatment-naive adults showed that RAL and dolutegravir (DTG) were equally effective and had similar safety profiles.11 ACTG A5257 compared RAL to ATV/r and darunavir/ritonavir; all regimens had equivalent virologic efficacy, but RAL had better tolerability.12 The ONCEMRK study compared RAL 1,200 mg once daily (taken as two 600-mg RAL HD tablets) to RAL 400 mg twice daily in treatment-naive adults. Once-daily dosing with RAL 1,200 mg (taken as two 600-mg HD tablets) was found to be as effective as dosing with RAL 400 mg twice daily. Discontinuation rates due to AEs were not different between the two groups.13 Once-daily dosing of RAL using the HD tablets was approved by the FDA for adults and children weighing ≥40 kg who are either treatment naive or virologically suppressed on a twice-daily RAL regimen.
RAL was studied in infants, children, and adolescents in IMPAACT P1066, an open-label trial that evaluated PK, safety, tolerability, and efficacy. In 96 participants aged 2 to 18 years who were mostly antiretroviral therapy (ART) experienced, 79.1% of the patients achieved a favorable viral load response (i.e., viral loads <400 copies/mL or ≥1 log10 decline in viral load) while receiving the currently recommended dose of RAL. Infants and toddlers aged ≥4 weeks to <2 years also were enrolled in IMPAACT P1066 and received treatment with RAL oral suspension. At Weeks 24 and 48, 61% of the participants (14 of 23 infants and toddlers) had HIV viral loads14-16 <400 copies/mL.
A systematic review of observational and clinical trials published on the effectiveness and safety of RAL and DTG for treating children and adolescents with HIV was conducted by the World Health Organization. The authors concluded that both medications are safe and effective as preferred regimens.17
Efficacy and Pharmacokinetics of Once-Daily Dosing in Children and Adults
RAL PK exhibit considerable intrasubject and intersubject variability.18,19 Current PK targets are based on results from a clinical trial in adults (QDMRK) in which treatment-naive patients with HIV were randomized to receive RAL 800 mg once daily or RAL 400 mg twice daily. After 48 weeks of treatment, the percent of patients who achieved HIV RNA viral loads <50 copies/mL was 83% in the once-daily group, compared with 89% in the twice-daily group. Patients in the once-daily arm with Ctrough concentrations <45 nM (20 ng/mL) were at greater risk of experiencing treatment failure.18,19 Overall drug exposures were similar in both groups, but the association between higher risk of treatment failure and lower Ctrough concentrations suggests that maintaining RAL trough plasma concentrations >45 nM (20 ng/mL) is important for efficacy.18,19
The highest concentration (Cmax) is approximately six times higher in patients receiving RAL 1,200 mg once daily than in those receiving RAL 400 mg twice daily, with a twofold higher area under the curve (AUC). Although modeling and simulations for pediatric patients indicate that PK targets are met using the once-daily RAL 1,200-mg dose, no clinical data exist on the use of this dose in children weighing <50 kg. Six children in IMPAACT P1066 had drug exposures that were similar to those observed in ONCEMRK, but all six children weighed >50 kg. Dose-related central nervous system toxicities—such as insomnia or hyperactivity—may occur in children who are exposed to very high concentrations of RAL.7
Efficacy and Pharmacokinetics in Children
IMPAACT P1066 evaluated the PK, safety, and efficacy of RAL in treatment-experienced children aged 4 weeks to 18 years. A summary of RAL steady-state PK parameters, following administration of the recommended twice-daily doses (approximately 6 mg/kg twice daily), can be found in Table A below.15,16
Body Weight | Formulation | Dose | Na | Geometric Mean (% CVb) AUC0-12h (μM●h)c,d | Geometric Mean (% CVb) C12h (nM)c,d |
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≥25 kg | Film-coated tablet | 400 mg twice daily | 18 | 14.1 (121%) | 233 (157%) |
≥25 kg | Chewable tablet | Weight-based dosinge | 9 | 22.1 (36%) | 113 (80%) |
11 kg to <25 kg | Chewable tablet | Weight-based dosinge | 13 | 18.6 (68%) | 82 (123%) |
3 kg to <20 kg | Oral suspension | Weight-based dosinge | 19 | 24.5 (43%) | 113 (69%) |
a Number of patients with intensive PK results at the final recommended dose
b Geometric coefficient of variation
c Pharmacokinetic & targets for film-coated tablets and chewable tablets: AUC0–12h 14–25 µM·h (6–11 mg·h/L); C12h nM ≥33 nM (14.7 ng/mL)
dPharmacokinetic targets for oral suspension: AUC0–12h 14–45 µM·h (6–20 mg·h/L); C12h nM ≥75 nM (33.3 ng/mL)
eTo approximate 6 mg/kg twice daily
Key: AUC = area under the curve; AUC0–12h = AUC from time zero to 12 hours after drug administration; C12h = concentration at 12 hours (trough); CV = coefficient of variation
Children Aged 2 Years to 18 Years
IMPAACT P1066 was a Phase 1/2 open-label, multicenter study that evaluated the PK profile, safety, tolerability, and efficacy of various formulations of RAL in ART-experienced children and adolescents with HIV aged 2 to 18 years. RAL was administered in combination with an optimized background ARV regimen.16,20 Subjects received either the RAL 400-mg, film-coated tablet formulation twice daily (patients aged 6–18 years and weighing ≥25 kg) or the chewable tablet formulation at a dose of RAL 6 mg/kg twice daily (patients aged 2 years to <12 years). In IMPAACT P1066, the initial dose-finding stage included an intensive PK evaluation in various age cohorts (Cohort 1: 12 years to <19 years; Cohort 2: 6 years to <12 years; Cohort 3: 2 years to <6 years). Doses were selected with the aim of achieving target PK parameters that were similar to those seen in adults: PK targets were a geometric mean (GM) AUC0–12h of 14 µM·h to 25 µM·h and a GM 12-hour concentration (C12h) >33 nM. Additional participants were then enrolled in each age cohort to evaluate the long-term efficacy, tolerability, and safety of RAL.
A total of 126 treatment-experienced participants were enrolled, with 96 participants receiving the final recommended dose of RAL. Only treatment-experienced patients were eligible to enroll, and the optimized regimen was determined by the site investigators. Adolescents tended to be more treatment experienced and have more advanced disease than those in the younger cohorts, with 75% having the Centers for Disease Control and Prevention Category B or C classification of HIV infection. Ninety-six participants completed 48 weeks of treatment. Seventy-nine percent of participants achieved HIV RNA <400 copies/mL, and 57% of participants achieved HIV RNA <50 copies/mL, with a mean CD4 T lymphocyte (CD4) count increase16 of 156 cells/mm3 (4.6%). Among 36 subjects who experienced virologic failure, the development of drug resistance and/or poor adherence were contributing factors. Genotypic resistance data were available for 34 patients who experienced virologic failure, and RAL-associated mutations were detected in 12 out of 34 of those patients. The frequency, type, and severity of AEs through Week 48 were comparable to those observed in adult studies. AEs were commonly reported, but few serious AEs were considered to be drug related. Patients with AEs that were considered to be drug related included one patient with Grade 3 psychomotor hyperactivity, abnormal behavior, and insomnia, as well as one patient with a Grade 2 allergic rash on Day 17 and Grade 3 ALT and Grade 4 AST laboratory elevations after Day 122. There were no discontinuations due to AEs and no drug-related deaths.16 Overall, RAL was well tolerated when administered as a film-coated tablet twice daily in subjects aged 6 years to <19 years and as chewable tablets at a dose of approximately 6 mg/kg twice daily in subjects aged 2 years to <12 years, with favorable virologic and immunologic responses.21
Children Aged ≥4 Weeks to <2 Years
IMPAACT P1066 studied 26 infants and toddlers aged 4 weeks to <2 years who were administered the granules for RAL oral suspension in combination with an optimized background ARV regimen. All subjects had previously received ARV drugs to prevent perinatal transmission and/or treat HIV, and 69% had baseline plasma HIV RNA exceeding 100,000 copies/mL. PK targets for Cohort IV (6 months to <2 years) and Cohort V (4 weeks to <6 months) were modified to a GM AUC0–12h of 14 µM·h to 45 µM·h and a GM C12h ≥75 nM (33.3 ng/mL). These targets were modified so that an estimated >90% of patients would have C12h above the 45 nM threshold. By Week 48, two subjects experienced AEs that were thought to be related to the study drug: one patient experienced a serious erythematous rash that resulted in permanent discontinuation of RAL, and one patient experienced immune reconstitution inflammatory syndrome. Virologic success, defined as ≥1 log10 decline in HIV RNA or <400 copies/mL at 48 weeks, was achieved in >87% of participants. At 48 weeks of follow up, 45.5% of subjects had HIV RNA <50 copies/mL and mean CD4 count increases of 527.6 cells/mm3 (7.3%). Four subjects in Cohort 4 experienced virologic failure by Week 48, and one participant had a RAL-associated resistance mutation. Overall, the granules for oral suspension, at a dose of approximately RAL 6 mg/kg twice daily, were well tolerated and had good efficacy.15
Long-Term Follow Up in Children
The IMPAACT P1066 study team reported results regarding the safety and efficacy of different RAL formulations at 240 weeks in children enrolled in this multicenter trial.22 Eligible participants were children aged 4 weeks to 18 years who had previously been treated with ART and who were experiencing virologic failure at the time of enrollment. RAL was added to an optimized ARV regimen in all participants. RAL was well tolerated, and few serious clinical or laboratory safety events were noted during the study.22
The proportion of participants who achieved virologic success at 240 weeks varied by the RAL formulation used: 19 of 43 children (44.2%) who received RAL 400-mg tablets; 24 of 31 children (77.4%) who received chewable tablets; and 13 of 15 children (86.7%) who received the oral granules for suspension. RAL resistance was documented in 19 of 50 patients (38%) who experienced virologic rebound after initial suppression. These results suggest that younger children with less treatment experience are more likely to have sustained virologic suppression, whereas older children with an extensive treatment history are more likely to experience treatment failure and develop resistance to RAL. Poor adherence among adolescents may have contributed to the lower efficacy observed in older children who received the RAL 400-mg tablets.22
Neonates Aged <4 Weeks
RAL is metabolized by UGT1A1, the same enzyme that is responsible for the elimination of bilirubin. UGT enzyme activity is low at birth, and RAL elimination is prolonged in neonates. Washout PKs of RAL in neonates born to pregnant women with HIV were studied in IMPAACT P1097.23 The neonatal plasma half-life of RAL was highly variable, ranging from 9.3 to 184 hours. This suggests that neonatal development may impact UGT1A1 enzyme activity, redistribution, and/or enterohepatic recirculation of RAL. RAL competes with unconjugated bilirubin for albumin binding sites. When RAL plasma concentrations are extremely high, unconjugated bilirubin may be displaced from albumin by RAL and cross the blood–brain barrier, leading to bilirubin-induced neurologic dysfunction. The effect of RAL on neonatal bilirubin binding is unlikely to be clinically significant, unless concentrations that are 50-fold to 100-fold higher than typical peak concentrations are reached (approximately 5,000 ng/mL).24
IMPAACT P1110 was a Phase 1, multicenter trial that enrolled full-term neonates with or without in utero RAL exposure at risk of acquiring HIV. RAL-exposed neonates were those whose mothers received RAL within 2 to 24 hours of delivery. For RAL-exposed neonates, the initial dose of RAL was delayed until 12 to 60 hours after delivery. The study design included two cohorts: Cohort 1 infants received two RAL doses that were administered 1 week apart, and Cohort 2 infants received daily RAL doses for the first 6 weeks of life. PK data from Cohort 1 and from older infants and children were combined in a population PK model, and simulations were used to select the following RAL dosing regimen for evaluation in infants in Cohort 2: RAL 1.5 mg/kg daily, starting within 48 hours of life and continuing through Day 7; RAL 3 mg/kg twice daily on Days 8 to 28 of life; and RAL 6 mg/kg twice daily after 4 weeks of age.25 Protocol exposure targets for each subject were AUC0–24hr 12 mg·h/L to 40 mg·h/L, AUC0–12hr 6 mg·h/L to 20 mg·h/L, and C12h or C24h >33 ng/mL. Safety was assessed using clinical and laboratory evaluations.23,26,27
Twenty-six RAL-naive infants and 10 RAL-exposed infants were enrolled in Cohort 2; 25 RAL-naive infants and 10 RAL-exposed infants had evaluable PK results and safety data. Results for the RAL-naive infants and RAL-exposed infants who were enrolled in Cohort 2 are contained in Table B below.27
Table B. Raltegravir Pharmacokinetic Parameters for Raltegravir-Naive and Raltegravir-Exposed Neonates | |
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Daily RAL was safe and well tolerated during the first 6 weeks of life. Infants were treated for up to 6 weeks from birth and followed for a total of 24 weeks. All GM protocol exposure targets were met. In some infants, AUC0–24h following the initial dose was slightly above the target range, but this is considered acceptable given the rapid increase in RAL metabolism during the first week of life. The PK targets and the safety guidelines were met for both RAL-naive and RAL-exposed infants in Cohort 2 using the specified dosing regimen. No drug-related clinical AEs were observed. Three laboratory AEs were reported among the RAL-naive infants: Grade 4 transient neutropenia occurred in one infant who received a zidovudine-containing regimen; two bilirubin elevations (one Grade 1 and one Grade 2) were considered nonserious and did not require specific therapy.7 Among the RAL-exposed infants, four infants exhibited Grade 3 or 4 toxicities: anemia in one infant, neutropenia in one infant, and hyperbilirubinemia in two infants. No specific therapy was required to treat these toxicities, and no infants required phototherapy or exchange transfusion for hyperbilirubinemia.
Results from IMPAACT P1110 confirmed the PK modeling and simulation submitted for FDA approval and labeling. Neonates born to mothers who received RAL 2 to 24 hours prior to delivery should have their first dose of RAL delayed until 24 to 48 hours after birth.26,27 The timing of administration of the initial dose of RAL to infants born to patients receiving DTG- or bictegravir-containing regimens has not been studied. In a single case report of a neonate born to a mother receiving an intensified regimen of DTG 50 mg twice daily for viremia close to the time of delivery, prolonged neonatal DTG concentrations were observed.28 These findings suggest that a similar delay in the first dose of RAL until 24 to 48 hours after birth may be indicated in neonates born to patients receiving an INSTI-containing oral regimen to avoid potential toxicity. Results of ongoing studies IMPAACT 2023 (DTG neonatal PK and safety study) and IMPAACT 2026 (washout PK in infants born to mothers receiving bictegravir) may provide PK data that can inform future recommendations.
The current RAL dosing regimen with two dose changes in the first month of life may be challenging for some families. To simplify medication teaching and minimize dosing changes, some experts increase to the 3 mg/kg twice-daily dose on Day 4 or 5 of life. Because many infants receiving RAL as part of presumptive HIV therapy will have a longer hospital stay following birth by cesarean section, this dosing change can generally be made at the time of hospital discharge.
RAL can be safely administered to full-term infants using the daily dosing regimen that was studied in IMPAACT P1110. This regimen is not recommended for use in preterm infants. RAL elimination kinetics in preterm and low-birth-weight neonates after maternal dosing was studied in IMPAACT P1097.29 Sixteen mothers and their 18 low-birth-weight neonates (<2.5 kg) were enrolled. Median (range) RAL elimination half-life was 24.4 hours (10.1–83) hours (n = 17). A PK model incorporating slower clearance in preterm neonates demonstrated that a reduction in RAL dosing is required in this population.29
Two case reports of preterm infants who received RAL to prevent perinatal transmission have been published.30,31 These case reports involved one infant born at a gestational age of 24 weeks and 6 days who weighed 800 g and another infant born at 33 weeks gestation who weighed 1,910 g. In both infants, intermittent dosing of RAL was done using real-time therapeutic drug monitoring in the neonatal intensive care unit.30,31 Less-frequent dosing was required because RAL elimination was significantly delayed in these preterm infants. RAL PKs and safety must be studied in preterm infants before RAL can be safely used without real-time PK monitoring in this population.
Formulations
The PK of RAL in adult patients with HIV who swallowed intact 400-mg tablets were compared with those observed in patients who chewed the 400-mg, film-coated tablets because of swallowing difficulties. Drug absorption was significantly higher among patients who chewed the tablets, although the palatability was rated as poor.32 In adult volunteers, the PK of RAL 800 mg taken once daily by chewing was compared with the PK of two doses of RAL 400 mg taken every 12 hours by swallowing. Participants who took RAL by chewing had significantly higher drug exposure and reduced PK variability than those who swallowed whole tablets according to current recommendations.33 According to the manufacturer, the film-coated tablets must be swallowed whole.
The RAL chewable tablet and oral suspension have higher oral bioavailability than the 400-mg, film-coated tablet, according to a comparative study in healthy adult volunteers.34 Compared with the RAL 400-mg tablet formulation, the RAL 600-mg tablet has higher relative bioavailability.7,35 Interpatient and intrapatient variability for PK parameters of RAL are considerable, especially with the film-coated tablets.7,36 Because of differences in the bioavailability of various formulations, the dosing recommendations for each formulation differ, and the formulations are not interchangeable. When prescribing RAL, clinicians should refer to the appropriate dosing table for the chosen formulation. The use of RAL chewable tablets as dispersible tablets in children aged <2 years has been studied in IMPAACT P1101 for infants and toddlers with TB/HIV coinfection who received rifampin as part of their TB treatment. The use of RAL chewable tablets dispersed in water at a dose of RAL 12 mg/kg per dose twice daily safely achieved PK targets.2,37 The RAL chewable tablets are now approved for use in infants and young children 4 weeks of age and older and weighing at least 2 kg.38 An in vitro evaluation demonstrated that the chewable tablets are stable in various liquids, including water, apple juice, and breast milk.38 The chewable tablets may be crushed and mixed with a small amount of liquid to facilitate administration (see Special Instructions above).
Palatability was evaluated as part of IMPAACT P1066. Both chewable tablets and oral granules for suspension were thought to have acceptable palatability. Seventy-three percent of those surveyed reported no problems with chewable tablets; 82.6% reported no problems with administering the oral granules.15,16 The acceptability and feasibility of administering RAL granules for oral suspension in a low-resource setting has been studied in clinics in South Africa and Zimbabwe. With proper training by health care personnel, caregivers were able to prepare the suspension safely and accurately.39,40
References
- Mills A, Myers L, Raudenbush C, et al. A health literate patient-focused approach to the redesign of the raltegravir (ISENTRESS) pediatric kit and instructions for use. Pediatr Infect Dis J. 2022;41(1):51-56. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34694252.
- Meyers T, Samson P, Acosta EP, et al. Pharmacokinetics and safety of a raltegravir-containing regimen in HIV-infected children aged 2–12 years on rifampicin for tuberculosis. AIDS. 2019;33(14):2197-2203. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31689263.
- Krogstad P, Samson P, Acosta EP, et al. Pharmacokinetics and safety of a raltegravir-containing regimen in children aged 4 weeks to 2 years living with human immunodeficiency virus and receiving rifampin for tuberculosis. J Pediatric Infect Dis Soc. 2021;10(2):201-204. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32448902.
- van der Veer MA, Jacobs TG, Bukkems LH, et al. Pharmacokinetic interaction between raltegravir and rifampicin in an infant with HIV exposed to active TB: a case report. Antivir Ther. 2022;27(4):13596535221119932. Available at: https://www.ncbi.nlm.nih.gov/pubmed/36062614.
- Thomas M, Hopkins C, Duffy E, et al. Association of the HLA-B*53:01 allele with drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome during treatment of HIV infection with raltegravir. Clin Infect Dis. 2017;64(9):1198-1203. Available at: https://pubmed.ncbi.nlm.nih.gov/28369189.
- Thomas SJ, Kilgore JT, Becken BA, et al. Raltegravir-associated drug-reaction with eosinophilia and systemic symptoms syndrome in a pediatric patient without characteristic human leukocyte antigen B*57:01 or B*53:01 alleles. J Pediatric Infect Dis Soc. 2021;10(3):363-366. Available at: https://pubmed.ncbi.nlm.nih.gov/32766769.
- Raltegravir (Isentress ) [package insert]. Food and Drug Administration. 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022145s042,203045s016,205786s008lblrpl.pdf.
- Lennox JL, DeJesus E, Lazzarin A, et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet. 2009;374(9692):796-806. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19647866.
- DeJesus E, Rockstroh JK, Lennox JL, et al. Efficacy of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected patients: week-192 overall and subgroup analyses from STARTMRK. HIV Clin Trials. 2012;13(4):228-232. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22849964.
- Rockstroh JK, DeJesus E, Lennox JL, et al. Durable efficacy and safety of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected patients: final 5-year results from STARTMRK. J Acquir Immune Defic Syndr. 2013;63(1):77-85. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23412015.
- Raffi F, Jaeger H, Quiros-Roldan E, et al. Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2013;13(11):927-935. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24074642.
- Lennox JL, Landovitz RJ, Ribaudo HJ, et al. Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial. Ann Intern Med. 2014;161(7):461-471. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25285539.
- Cahn P, Sax PE, Squires K, et al. Raltegravir 1200 mg once daily vs. 400 mg twice daily, with emtricitabine and tenofovir disoproxil fumarate, for previously untreated HIV-1 infection: week 96 results from ONCEMRK, a randomized, double-blind, noninferiority trial. J Acquir Immune Defic Syndr. 2018;78(5):589-598. Available at: https://pubmed.ncbi.nlm.nih.gov/29771789.
- Briz V, Leon-Leal JA, Palladino C, et al. Potent and sustained antiviral response of raltegravir-based highly active antiretroviral therapy in HIV type 1-infected children and adolescents. Pediatr Infect Dis J. 2012;31(3):273-277. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22330165.
- Nachman S, Alvero C, Acosta EP, et al. Pharmacokinetics and 48-week safety and efficacy of raltegravir for oral suspension in human immunodeficiency virus type-1-infected children 4 weeks to 2 years of age. J Pediatric Infect Dis Soc. 2015;4(4):e76-83. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26582887.
- Nachman S, Zheng N, Acosta EP, et al. Pharmacokinetics, safety, and 48-week efficacy of oral raltegravir in HIV-1-infected children aged 2 through 18 years. Clin Infect Dis. 2014;58(3):413-422. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24145879.
- Townsend CL, O’Rourke J, Milanzi E, et al. Effectiveness and safety of dolutegravir and raltegravir for treating children and adolescents living with HIV: a systematic review. J Int AIDS Soc. 2022;25(11):e25970. Available at: https://pubmed.ncbi.nlm.nih.gov/36377082.
- Rizk ML, Hang Y, Luo WL, et al. Pharmacokinetics and pharmacodynamics of once-daily versus twice-daily raltegravir in treatment-naive HIV-infected patients. Antimicrob Agents Chemother. 2012;56(6):3101-3106. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22430964.
- Rizk ML, Du L, Bennetto-Hood C, et al. Population pharmacokinetic analysis of raltegravir pediatric formulations in HIV-infected children 4 weeks to 18 years of age. J Clin Pharmacol. 2015;55(7):748-756. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25753401.
- Larson KB, King JR, Acosta EP. Raltegravir for HIV-1 infected children and adolescents: efficacy, safety, and pharmacokinetics. Adolesc Health Med Ther. 2013;4:79-87. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24600298.
- Tuluc F, Spitsin S, Tustin NB, et al. Decreased PD-1 expression on CD8 lymphocyte subsets and increase in CD8 Tscm cells in children with HIV receiving raltegravir. AIDS Res Hum Retroviruses. 2016;33:133-142. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27615375.
- Nachman S, Alvero C, Teppler H, et al. Safety and efficacy at 240 weeks of different raltegravir formulations in children with HIV-1: a phase 1/2 open label, non-randomised, multicentre trial. Lancet HIV. 2018;5(12):e715-e722. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30527329.
- Clarke DF, Acosta EP, Rizk ML, et al. Raltegravir pharmacokinetics in neonates following maternal dosing. J Acquir Immune Defic Syndr. 2014;67(3):310-315. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25162819.
- Clarke DF, Wong RJ, Wenning L, Stevenson DK, Mirochnick M. Raltegravir in vitro effect on bilirubin binding. Pediatr Infect Dis J. 2013;32(9):978-980. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23470680.
- Clarke DF, Mirochnick M, Acosta EP, et al. Use of modeling and simulations to determine raltegravir dosing in neonates: a model for safely and efficiently determining appropriate neonatal dosing regimens: IMPAACT P1110. J Acquir Immune Defic Syndr. 2019;82(4):392-398. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31658182.
- Lommerse J, Clarke D, Kerbusch T, et al. Maternal-neonatal raltegravir population pharmacokinetics modeling: implications for initial neonatal dosing. CPT Pharmacometrics Syst Pharmacol. 2019;8(9):643-653. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31215170.
- Clarke DF, Acosta EP, Cababasay M, et al. Raltegravir (RAL) in neonates: dosing, pharmacokinetics (PK), and safety in HIV-1-exposed neonates at risk of infection (IMPAACT P1110). J Acquir Immune Defic Syndr. 2020;84(1):70-77. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31913995.
- Jacobs TG, Schouwenburg S, Penazzato M, et al. What babies need: accelerating access to current and novel antiretroviral drugs in neonates through pharmacokinetic studies. Lancet HIV. 2022;9(9):e649-e657. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35863363.
- Clarke DF, Lommerse J, Acosta EP, et al. Impact of low birth weight and prematurity on neonatal raltegravir pharmacokinetics: IMPAACT P1097. J Acquir Immune Defic Syndr. 2020;85:626-634. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32925360.
- Trahan MJ, Lamarre V, Metras ME, Kakkar F. Use of triple combination antiretroviral therapy with raltegravir as empiric HIV therapy in the high-risk HIV-exposed newborn. Pediatr Infect Dis J. 2018;38(4):410-412. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30882734.
- Kreutzwiser D, Sheehan N, Dayneka N, et al. Therapeutic drug monitoring guided raltegravir dosing for prevention of vertical transmission in a premature neonate born to a woman living with perinatally acquired HIV. Antivir Ther. 2017;22(6):545-549. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28198351.
- Cattaneo D, Baldelli S, Cerea M, et al. Comparison of the in vivo pharmacokinetics and in vitro dissolution of raltegravir in HIV patients receiving the drug by swallowing or by chewing. Antimicrob Agents Chemother. 2012;56(12):6132-6136. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22964253.
- Cattaneo D, Cossu MV, Fucile S, et al. Comparison of the pharmacokinetics of raltegravir given at 2 doses of 400 mg by swallowing versus one dose of 800 mg by chewing in healthy volunteers: a randomized, open-label, 2-period, single-dose, crossover phase 1 study. Ther Drug Monit. 2015;37(1):119-125. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24988438.
- Brainard D, Gendrano N, Jin B, et al. A pharmacokinetic comparison of adult and pediatric formulations of RAL in healthy adults. Presented at: Conference on Retroviruses and Opportunistic Infections (CROI); 2010. San Francisco, CA.
- Krishna R, Rizk ML, Larson P, Schulz V, Kesisoglou F, Pop R. Single- and multiple-dose pharmacokinetics of once-daily formulations of raltegravir. Clin Pharmacol Drug Dev. 2018;7(2):196-206. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28419778.
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- Krogstad P, Samson P, Acosta E, et al. Pharmacokinetics of raltegravir in HIV/TB cotreated infants and young children. Presented at: Conference on Retroviruses and Opportunistic Infections 2020. Boston, MA.
- Teppler H, Thompson K, Chain A, Mathe M, Nachman S, Clarke D. Crushing of raltegravir (RAL) chewable tablets for adminstration in infants and young children. Presented at: International Workshop on HIV Pediatrics; 2017. Paris, France.
- Archary M, Zanoni BC, Lallemant M, Suwannaprom P, Clarke D, Penazzato M. Acceptability and feasibility of using raltegravir oral granules for suspension for the treatment of neonates in a low resource setting. Pediatr Infect Dis J. 2020;39(1):57-60. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31815839.
- Katirayi L, Stecker C, Andifasi P, et al. Optimising neonatal antiretroviral therapy using raltegravir: a qualitative analysis of healthcare workers’ and caregivers’ BMJ Paediatr Open. 2022;6(1). Available at: https://www.ncbi.nlm.nih.gov/pubmed/36053612.
Integrase Inhibitors
Raltegravir
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Tablet: 400 mg (film-coated poloxamer tablet) High-Dose (HD) Tablet: 600 mg (film-coated poloxamer tablet) Chewable Tablets: 100 mg (scored) and 25 mg Granules for Oral Suspension: Single-use packet of 100 mg of raltegravir, suspended in 10 mL of water for a final concentration of 10 mg/mL Film-coated tablets, chewable tablets, and oral suspension are not interchangeable. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dosing Recommendations | Selected Adverse Events | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Note: No dosing information is available for preterm infants or infants weighing <2 kg at birth. See Table 13 in Antiretroviral Management of Newborns with Perinatal HIV Exposure or HIV Infection for information about using raltegravir (RAL) for the prevention of perinatal HIV transmission. Neonate (Weighing ≥2 kg) Dosea, b RAL Oral Suspension Dosing Table for Full-Term Neonates from Birth to Age 4 Weeks Neonates Aged ≥37 Weeks and Weighing ≥2 kg
Note: If the mother has taken RAL 2–24 hours prior to delivery, the neonate’s first dose should be delayed until 24–48 hours after birth. Infant >4 Weeks of Age and Child (Weighing ≥3 kg to <20 kg) Dose
Raltegravir Oral Suspension Dosing Table for Patients Aged >4 Weeksa Note: The maximum dose of oral suspension is 10 mL (RAL 100 mg) twice daily.
Child and Adolescent Dose for Chewable Tablets, Film-Coated Tablets, and HD Tablets Children Weighing ≥3 kg
Children and Adolescents Weighing ≥40 kg
Chewable Tablet Dosing Tablea Note: The maximum dose of chewable tablets is RAL 300 mg twice daily.
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Special Instructions | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Metabolism/Elimination | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Raltegravir Dosing in Patients with Hepatic Impairment
Raltegravir Dosing in Patients with Renal Impairment
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Efficacy and Pharmacokinetics in Children
Body Weight | Formulation | Dose | Na | Geometric Mean (% CVb) AUC0-12h (μM●h)c,d | Geometric Mean (% CVb) C12h (nM)c,d |
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≥25 kg | Film-coated tablet | 400 mg twice daily | 18 | 14.1 (121%) | 233 (157%) |
≥25 kg | Chewable tablet | Weight-based dosinge | 9 | 22.1 (36%) | 113 (80%) |
11 kg to <25 kg | Chewable tablet | Weight-based dosinge | 13 | 18.6 (68%) | 82 (123%) |
3 kg to <20 kg | Oral suspension | Weight-based dosinge | 19 | 24.5 (43%) | 113 (69%) |
a Number of patients with intensive PK results at the final recommended dose
b Geometric coefficient of variation
c Pharmacokinetic & targets for film-coated tablets and chewable tablets: AUC0–12h 14–25 µM·h (6–11 mg·h/L); C12h nM ≥33 nM (14.7 ng/mL)
dPharmacokinetic targets for oral suspension: AUC0–12h 14–45 µM·h (6–20 mg·h/L); C12h nM ≥75 nM (33.3 ng/mL)
eTo approximate 6 mg/kg twice daily
Key: AUC = area under the curve; AUC0–12h = AUC from time zero to 12 hours after drug administration; C12h = concentration at 12 hours (trough); CV = coefficient of variation
Neonates Aged <4 Weeks
Table B. Raltegravir Pharmacokinetic Parameters for Raltegravir-Naive and Raltegravir-Exposed Neonates | |
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