INDICATIONS

FDA

  • Treatment of HIV-1 infection in combination with other ARV agents in ART-experienced pts with evidence of HIV replication despite ongoing ART.
  • Treatment of HIV-1 infection in combination with other ARV agents in ART-naive pts.

NON-FDA APPROVED USES

  • Substitution for other ARV agents due to drug toxicity or intolerance in pts on suppressive regimen (limited data)

FORMS

brand name

preparation

manufacturer

route

form

dosage^

cost*

Isentress

Raltegravir (RAL)

Merck & Co., Inc.

Oral

tablet

400 mg

$17.91 per tab

Raltegravir (RAL)

Merck & Co., Inc.

Oral

chewable tablet

100 mg, 25 mg

$5.37, $1.34

Raltegravir (RAL)

Merck & Co., Inc.

Oral

suspension

100 mg per packet

TBA

*Prices represent cost per unit specified, are representative of "Average Wholesale Price" (AWP).
^Dosage is indicated in mg unless otherwise noted.

USUAL ADULT DOSING

  • Typical dosing: with or without food
    • 400 mg film-coated tablet twice daily OR
    • 300 mg chewable tablet* PO twice daily
  • In combination with all PIs, NRTIs, and NNRTIs: use standard dose (400 mg PO twice-daily)

*Note: chewable tablets are not interchangeable with film coated tablets. Avoid chewable tablets in patients with phenylketonuria.

PEDIATRIC DOSING

USUAL PEDIATRIC DOSING

  • Neonates (< 4 weeks): NOT approved for use (NOTE: UGT1A1 metabolism is immature in neonates; IMPAACT P1110 will study a neonatal dose in full term babies)
  • Infant/pediatric (≥4 weeks and weight 3 to < 20kg): Dosing using the oral granules for suspension (expected to be commercially available starting 3rd quarter of 2014); NOTE: PO suspension, PO chew tabs and PO tablets are NOT bioequivalent and dosing is not interchangeable
    • 3 to < 4 kg: 20 mg (1mL) PO twice daily
    • 4 to < 6 kg: 30 mg (1.5mL) PO twice daily
    • 6 to < 8 kg: 40 mg (2mL) PO twice daily
    • 8 to < 11 kg: 60 mg (3mL) PO twice daily
    • 11 to < 14 kg: 80 mg (4mL) PO twice daily
    • 14 to < 20 kg: 100 mg (5mL) PO twice daily (100mg/dose = max dose for PO suspension)
    • NOTE: dosing approximates 6 mg/kg/dose PO twice daily
  • Children 2 to < 12 y/o:
    • Chewable tablet dosing for Weight < 25 kg: (NOTE: CANNOT interchange with PO film coated tablets)
      • 11 to < 14 kg: 75 mg PO twice daily (3 x 25mg chew tabs/dose)
      • 14 to < 20 kg: 100 mg PO twice daily (1 x 100mg chew tab/dose)
      • 20 to < 28 kg: 150 mg PO twice daily (1.5 x 100mg chew tabs/dose)
      • 28 to < 40 kg: 200 mg PO twice daily (2 x 100mg chew tabs/dose)
      • ≥40 kg: 300 mg PO twice daily (3 x 100mg chew tabs/dose) (300mg/dose = max dose of chew tabs)
      • NOTE: dosing approximates 6 mg/kg/dose PO twice daily
    • Film coated tablet dosing for Weight ≥25 kg: (NOTE: CANNOT interchange with PO chew tabs)
      • 400 mg PO twice daily
  • Adolescent (≥12 y/o):
    • 400 mg film coated tablet PO twice daily

PEDIATRIC RENAL DOSING

  • No renal dosage adjustment necessary.

OTHER PEDIATRIC INFORMATION

  • Chew tabs and PO suspension have better bioavailability than film coated tablets, therefore, dosage formulations are NOT interchangeable.

RENAL DOSING

DOSING FOR GLOMERULAR FILTRATION OF 50-80

Usual dose.

DOSING FOR GLOMERULAR FILTRATION OF 10-50

No data. Usual dose likely.

DOSING FOR GLOMERULAR FILTRATION OF <10 ML/MIN

No data. Usual dose likely.

DOSING IN HEMODIALYSIS

No data. Dose post-HD on days of dialysis.

DOSING IN PERITONEAL DIALYSIS

No data.

DOSING IN HEMOFILTRATION

No data.

ADVERSE DRUG REACTIONS

GENERAL

  • Generally well tolerated with comparable ADR rates to placebo. Rates of discontinuation of therapy due to AEs were 2% with RAL+ optimized background therapy (OBT) and 1.4% with placebo + OBT.

OCCASIONAL

  • GI: nausea, diarrhea, flatulence
  • Headache
  • Dizziness
  • Fever (unclear association)
  • Pruritis
  • Creatine kinase elevation
  • Transaminase elevation (discontinue RAL with LFT elevation and drug rash)
  • CNS: e.g., depression, paranoia, and suicidal ideation and behaviors
  • Rash

RARE

  • Myopathy and rhabdomyolysis: CPK elevation (grade 3/4) more common in pts treated with RAL compared to EFV.
  • Malignancies (3.5% in RAL recipients at 48 weeks vs. 2.6% in placebo recipients; difference did not persist, but post FDA-approval surveillance for malignancies in progress)
  • Cerebellar ataxia
  • Thrombocytopenia
  • Severe rash (including SJS, TEN, and DRESS-Drug Rash with Eosinophilia and Systemic Symptoms)

DRUG INTERACTIONS

Drug-to-Drug Interactions

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.

Atazanavir (ATV)

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.

Efavirenz (EFV)

RAL AUC decreased by 36%, but Cmin not significantly affected.

Use standard dose RAL.

Etravirine

RAL PK unchanged. ETR AUC increased 10%.

Use standard dose

Fosamprenavir

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 unknown. Avoid unboosted FPV with RAL co-administration. Use FPV/r with close monitoring or consider alternative boosted PI with RAL co-administration.

Lopinavir/ritonavir

RAL Cmin decreased 30%.

Use standard dose

Maraviroc

RAL PK unchanged

Use standard dose

Methadone

No change in RAL and methadone PK.

Use standard dose.

Nevirapine

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

Rifabutin reduces RAL trough by 20%, but RAL AUC 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.

Ritonavir

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 becomes available.

Tacrolimus

No significant interaction.

Case series of favorable outcome in pts treated with RAL-based regimen s/p solid organ transplant on tacrolimus. Use standard dose.

Tenofovir

RAL AUC increased 49%

Standard dose.

Tipranavir/ritonavir

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 subgroup of pts who received TPV/r plus RAL relative to pts not receiving TPV/r. Hepatic necrolysis reported in 3 patients on TPV/r + RAL: monitor transaminases.

  • Not a substrate, inhibitor, or inducer of CYP3A4; therefore, significant drug interactions with CYP3A4 substrates, inhibitors, and inducers are unlikely. RAL is primarily metabolized by glucuronidation via the enzyme, UDP-glucuronosyltransferase (UGT) 1A1.

RESISTANCE

  • 2 pathways to resistance with mutations in integrase gene: (1) N155H + (E92Q,V151I, T97A, G163R, L74M) and (2) Q148K/R/H + (G140S/A, E138K).
  • Other pathways may exist, e.g. Y143R/C + (L74A/I, E92Q, T97A, I203M, S230R).
  • Evidence of cross resistance with elvitegravir (investigational integrase inhibitor). Q148 pathway leads to cross-resistance to S/GSK1349572 (investigational integrase inhibitor).
  • Integrase inhibitor genotypic and phenotypic resistance tests available. Genotype generally preferred, as it provides information about susceptibility/cross-resistance to investigational integrase inhibitors.

PHARMACOLOGY

MECHANISM

RAL inhibits integrase, an essential enzyme responsible for catalyzing the insertion of HIV DNA into the host genome.

PHARMACOKINETIC PARAMETERS

Absorption

Absolute bioavailability not established.

Metabolism and Excretion

Eliminated mainly by metabolism via a UGT1A1-mediated glucuronidation pathway. RAL-glucuronide and RAL are eliminated excreted in feces (51%) and urine (32%).

Protein Binding

83%

Cmax, Cmin, and AUC

Geometric mean AUC 0-12h and Cmin were 14.3 microM per hr and 142 nM, respectively. Efficacy not associated with Cmin, but In vitro, antiviral response associated with AUC/EC50.

T1/2

9 hrs. RAL exhibited a long residence time on the integrase/DNA complexes. Clinical trials evaluating once-daily RAL are underway.

Distribution

CNS to plasma ratio of 7.3%. RAL CSF concentrations exceeded IC50 of wild-type HIV.

DOSING FOR DECREASED HEPATIC FUNCTION

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.

PREGNANCY RISK

Category C: No human data. Animal developmental studies found a higher incidence of supernumerary ribs compared to control.

BREAST FEEDING COMPATIBILITY

No human data, but based on animal studies, RAL concentrated in breast milk.

COMMENTS

  • Pro:
    • First approved integrase inhibitor with no cross-resistance to currently approved ARVs.
    • Highly effective when used in combination with OBT in heavily treatment-experienced pts with extensive resistance to currently approved ARVs.
    • Good short-term safety and few drug interactions.
    • More rapid VL reduction at 4 and 8 wks and better tolerability vs. EFV in treatment naive-pts with comparable 96-wk results. Clinical significance of more rapid VL reduction unknown.
  • Con:
    • Unknown long-term safety.
    • Appears to have a lower barrier to resistance than boosted-PIs.
    • Data indicate cross-resistance with investigational integrase inhibitor elvitegravir, which may limit ability to sequence within integrase inhibitor class.

References

  1. Eron J, et al. CROI 2011. Abstract 150LB QDMRK, A Phase III Study of the Safety and Efficacy of Once Daily (QD) Versus Twice Daily (BID) Raltegravir (RAL) in Combination Therapy for Treatment-Naïve HIV-Infected Patients (Pts)

    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. Difference was largely driven by pts with high VL. Among those with VL >1000,000, 74.3% of once-daily group vs. 84.2% of twice-daily group had undetectable VL.

  2. Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. Available at
    http://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf. Accessed (04/23/14) [pages O-119 to O-122]

    Comment: DHHS guideline recommendations for raltegravir dosing in pediatrics.

  3. Markowitz M et al: Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J Acquir Immune Defic Syndr 46:125, 2007  [PMID:17721395]

    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 more common in the EFV arm than RAL counterparts.
    Rating: Important

  4. Steigbigel RT et al: Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med 359:339, 2008  [PMID:18650512]

    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.

  5. Grinsztejn B et al: Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. Lancet 369:1261, 2007  [PMID:17434401]

    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 genotypically or phenotypically resistant to at least 1 drug in each of 3 classes (NNRTIs, NRTIs, PIs). Baseline characteristics 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 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 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 ws; 54% taking any dose of RAL had VL <50.

  6. Markowitz M et al: Sustained antiretroviral effect of raltegravir after 96 weeks of combination therapy in treatment-naive patients with HIV-1 infection. J Acquir Immune Defic Syndr 52:350, 2009  [PMID:19648823]

    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 observed in RAL-treated pts.

  7. Eron JJ et al: Switch to a raltegravir-based regimen versus continuation of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1 and 2): two multicentre, double-blind, randomised controlled trials. Lancet 375:396, 2010  [PMID:20074791]

    Comment: SWITCHMRK 1 and 2 evaluated switch to RAL in ART-experienced pts who were virologically controlled on stable LPVr-based regimen. Pts had 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 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 importance of evaluating ART history and resistance before switching to regimen with lower barrier to resistance.

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Last updated: July 11, 2014