brand name | preparation | manufacturer | route | form | dosage^ | cost* |
Isentress | Raltegravir (RAL) | Merck & Co., Inc. | Oral | tablet | 400 mg | $34.70 per tab |
Raltegravir (RAL) | Merck & Co., Inc. | Oral | chewable tablet | 100 mg, 25 mg | $2.17, $8.68 | |
Raltegravir (RAL) | Merck & Co., Inc. | Oral | suspension | 100 mg per packet | $8.68 | |
Raltegravir (RAL) | Merck & Co., Inc. | Oral | tablet | 600 mg | $34.70 |
*Prices represent cost per unit specified, are representative of "Average Wholesale Price" (AWP).
^Dosage is indicated in mg unless otherwise noted.
*Note: chewable tablets are not interchangeable with film-coated tablets. Avoid chewable tablets in patients with phenylketonuria.
[11]Neonates ≥ 37 weeks GA and weight ≥ 2 kg: empiric treatment dose, dosing using the oral suspension
Infant/Pediatric Dosing (≥4 weeks of age):
NOTE: PO suspension, PO chew tabs and PO film-coated tablets are NOT bioequivalent and dosing is not interchangeable.
PO suspension, PO chew tabs and PO film-coated tablets are NOT bioequivalent and dosing is not interchangeable.
No data. Dose post-HD on days of dialysis.
No data.
No data.
Drug | Effect of Interaction | Recommendations/Comments |
Antacid (e.g., Maalox) | RAL AUC and Cmin decreased by 24% and 67%, respectively. | Avoid co-administration. Administer RAL 2-4 hours before antacid administration. |
With ATV/r, RAL AUC and Cmin increased 41% and 77%, respectively. With unboosted ATV 300 mg twice-daily + RAL 400 mg twice-daily resulted in ATV AUC and Cmin reduction of 17% and 29%, respectively. Mean QTc was not increased, but QRS interval increased 11 ms (range 2-25 ms). | Recommended dose ATV/r 300/100 mg once-daily plus RAL 400 mg twice daily. The clinical significance of QRS interval increase and lower ATV concentrations observed with ATV 300 mg twice-daily + RAL 400 mg twice-daily remains to be determined. With RAL co-administration, use boosted ATV/r 300/100 mg once daily. | |
RAL AUC decreased by 36%, but Cmin was not significantly affected. | Use standard dose RAL. | |
RAL PK is unchanged. ETR AUC increased 10%. | Use standard dose | |
RAL and APV AUC decreased 37% and 36%, respectively (with unboosted FPV). RAL AUC decreased 55% (with FPV/r 700/100 mg bid). | Clinical significance is unknown. Avoid unboosted FPV with RAL co-administration. Use FPV/r with close monitoring or consider alternative boosted PI with RAL co-administration. | |
RAL Cmin decreased 30%. | Use standard dose | |
RAL PK unchanged | Use standard dose | |
Methadone | No change in RAL and methadone PK. | Use standard dose. |
May decrease RAL serum concentrations. | Use standard dose RAL with close monitoring of virologic efficacy. | |
Omeprazole | RAL AUC and Cmin increased by 3-fold and 1.5-fold, respectively. | Unclear clinical significance. Use standard dose. |
Phenobarbital | Phenobarbital may significantly decrease RAL serum concentrations. | Avoid co-administration. Consider valproic acid or levetiracetam |
Phenytoin | Phenytoin may significantly decrease RAL serum concentrations. | Avoid co-administration. Consider valproic acid or levetiracetam |
Rifabutin reduces RAL trough by 20%, but RAL AUC is not affected. | Use RAL 400 mg twice daily plus rifabutin 300 mg once daily | |
Rifampin | Rifampin decreases RAL AUC and Cmin by 40% and 61%, respectively. | Increasing RAL to 800 mg twice daily resulted in adequate AUC, but Cmin was decreased by 53%. Limited clinical data. Avoid co-administration if possible. Consider rifabutin with RAL co-administration. |
RAL PK unchanged | Use standard dose | |
Sirolimus | Drug interaction unlikely | Case report of safe co-administration of RAL and sirolimus. Use standard dose. |
St John’s wort | May decrease RAL serum concentrations. | Avoid co-administration until PK data become available. |
Tacrolimus | No significant interaction. | Case series of favorable outcomes in pts treated with RAL-based regimen s/p solid organ transplant on tacrolimus. Use standard dose. |
RAL AUC increased 49% | Standard dose. | |
RAL Cmin decreased by 55%, but AUC decreased by 24% (NS). | Use with close monitoring of virologic efficacy. Clinical significance unclear; comparable efficacy observed in a subgroup of pts who received TPV/r plus RAL relative to pts not receiving TPV/r. Hepatic necrolysis was reported in 3 patients on TPV/r + RAL: monitor transaminases. |
RAL inhibits integrase, an essential enzyme responsible for catalyzing the insertion of HIV DNA into the host genome.
Absolute bioavailability not established. Compared to the 400 mg formulation, the 600 mg tablet formulation has higher relative bioavailability. Steady-state is generally reached in 2 days for both the 400 mg and 600 mg formulations.
AUC decreased by ~6% with high-fat meal (not clinically significant)
Eliminated mainly by metabolism via a UGT1A1-mediated glucuronidation pathway. RAL-glucuronide and RAL are eliminated excreted in feces (51%) and urine (32%).
83%
Geometric mean AUC 0-12h and Cmin were 14.3 microM per hr and 142 nM, respectively. Efficacy is not associated with Cmin, but In vitro, an antiviral response is associated with AUC/EC50.
9 hrs. RAL exhibited a long residence time on the integrase/DNA complexes. Clinical trials evaluating once-daily RAL are underway.
CNS to plasma ratio of 7.3%. RAL CSF concentrations exceeded IC50 of wild-type HIV.
No dosage adjustment is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of RAL has not been studied.
No human data, but based on animal studies, RAL concentrated in breast milk.
Comment: DHHS recommendations for dosing of raltegravir in pediatric patients.
Comment: Phase 1 dose-finding study of raltegravir in infants exposed to HIV infection. PK data from the first cohort of patients was included in population modeling and simulations to guide dosing for infants in a second cohort. The basis for weight-based dosing recommendations of raltegravir for full-term neonates.
Comment: The basis for recommendation to delay the first dose of raltegravir to a neonate until 1-2 days of age in neonates born to mothers who received raltegravir during pregnancy up until the point of delivery.
Comment: SWITCHMRK 1 and 2 evaluated switch to RAL in ART-experienced pts who were virologically controlled on stable LPVr-based regimen. Pts had a median of 5 previous ARVs. Patients randomized to switch LPV/r to RAL (n=350) or continue on LPV/r (n=352) while remaining on the same background ART, which included at least 2 NRTI. Switch to RAL resulted in lower cholesterol and triglycerides; however, at week 24, RAL did not demonstrate non-inferiority compared to LPV/r. 293 of 347 (84.4%) vs 319 of 352 (90.6%) pts had HIV RNA < 50 in RAL and LPVr groups, respectively; treatment difference -6.2 % (95%CI -11.2 to -1.3 ; NC = F). Demonstrates the importance of evaluating ART history and resistance before switching to the regimen with a lower barrier to resistance.
Comment: Randomized, double-blind, study of RAL vs EFV, both combined with TDF/FTC, in 198 ART-naive pts. At wk 96, 83% of RAL and 84% of EFV-treated pts achieved undetectable VL (< 50). As expected, lower CNS adverse events were observed in RAL-treated pts.
Comment: Randomized, double-blind studies of RAL vs. placebo, each with OBT, in 699 treatment-experienced - pts failing ARTs with HIV resistant to PIs, NNRTIs, and NRTIs. In a combined analysis, At 48 wks, 62.1 % taking RAL+ OBT vs 32.9 % taking placebo + OBT achieved VL <50 (p<0.001). CD4 increased by 84 in RAL group vs 37 in placebo group (p<0.001). In a sub-analysis, first use of ENF, DRV, or both in the OBT + RAL resulted in VL <50 in 82%, 68%, 80% of treated pts, respectively. In RAL treated pts with genotypic sensitivity score (GSS) of >/-0 , VL <50 achieved in 44% and 71%, respectively. No difference in virologic suppression between GSS score of 1 and 2 or greater in RAL treated pts, but may have been due to partial activity of the OBT.
Comment: Randomized trial of ART-naive pts (n=198) comparing RAL (100, 200, 400, and 600 twice daily) to EFV, both in combination with TDF/FTC. Baseline VL 4.6-4.8 log and CD4 271-314. VL < 50 achieved in 85% to 88% of pts across all arms at 48 wks. At 96 wks, RAL continued to be effective with virologic suppression (< 50 c/mL) observed in 83% vs 84% of RAL and EFV-treated pts, respectively. The efficacy was comparable between EFV and RAL arms across all dosages. However, a more rapid reduction in VL to < 50 was observed in the RAL compared to EFV arm at wks 4 and 8. CNS AEs were more common in the EFV arm than their RAL counterparts.
Rating: Important
Comment: Randomized, double-blind, multi-dose (200, 400, 600 mg twice daily) placebo-controlled trial of RAL in pts with multiple-drug resistant HIV. All pts were genotypically or phenotypically resistant to at least 1 drug in each of 3 classes (NNRTIs, NRTIs, PIs). Baseline characteristics are comparable between the 2 groups. Of the 133 pts randomized to RAL + OBR, VL= 4.7 log, CD4= 240, and 9.9 yrs of prior ARTs. OBR contained a median of 4 ARVs with 45 (36%) receiving ENF. At 24-wks, VL< 50 VL was achieved in 65-67% and 13% of RAL and control pts, respectively. Due to the virologic benefit seen in the RAL arm, all pts (including those in the placebo arm) were switched to RAL 400 mg twice daily after 24 wks. Overall, those who had achieved virologic suppression on RAL at 24 wks had largely maintained it to 48 vs 54% taking any dose of RAL had VL < 50.
Comment: Phase 3, double-blind, noninferiority trial comparing raltegravir 1200 mg once daily with raltegravir 400 mg BID plus emtricitabine and tenofovir disoproxil fumarate in 797 treatment-naive patients living with HIV for 96 weeks. Discontinuations occurred in 1.1% of participants due to lack of efficacy in both groups and adverse events in 1.3% compared to 2.3% in once daily and twice daily respectively. There was a nonsignificant treatment difference of 1.4% in participants who achieved HIV-1 RNA < 40 copies/milliliter by week 96. Adverse events were found to be similar for the two groups.
Comment: Randomized study of RAL 800 mg once-daily vs. RAL 400 mg twice daily, each with TDF/FTC, in 770 ART-naive pts. At 48 wks, 83.2 % taking RAL once daily vs 88.9% RAL twice daily achieved VL < 50. Treatment difference of -5.7% (CI -10.7%, -0.83%) did not meet criteria for non-inferiority. The difference was largely driven by pts with high VL. Among those with VL >1000,000, 74.3% of the once-daily group vs. 84.2% of the twice-daily group had undetectable VL.
Comment: DHHS guidelines for HIV in pregnancy and perinatal transmission prevention.