Actualizado
Dic. 30, 2021
Reviewed
Dic. 30, 2021

Integrase Inhibitors

Raltegravir (Isentress, RAL)

Animal Studies

Carcinogenicity

Raltegravir (RAL) was neither mutagenic nor clastogenic in a series of in vitro and animal in vivo screening tests. Long-term carcinogenicity studies of RAL in mice did not show any carcinogenic potential at systemic exposures that were 1.8-fold (in females) or 1.2-fold (in males) greater than human exposure at the recommended dose. Treatment-related squamous cell carcinoma of the nose/nasopharynx was observed in female rats with prolonged exposures threefold higher than seen in humans who received the recommended adult dose. These tumors were possibly the result of local irritation and inflammation due to local deposition and/or aspiration of the drug in the mucosa of the nose/nasopharynx during dosing. No tumors of the nose/nasopharynx were observed in rats with systemic exposures that were 1.7-fold (in males) or 1.4-fold (in females) greater than the exposure observed in humans who received the recommended dose of RAL.1

Reproduction/Fertility

RAL had no adverse effects on the fertility of male or female rats at exposures up to threefold higher than the exposures seen in humans who received the recommended adult dose.

Teratogenicity/Adverse Pregnancy Outcomes

No treatment-related effects on embryonic/fetal survival or fetal weights were observed in studies where RAL was administered to rats and rabbits at doses that produced systemic exposures approximately threefold to fourfold higher than the exposures seen in humans who received the recommended daily dose. In rabbits, no treatment-related external, visceral, or skeletal changes were observed. However, treatment-related increases in the incidence of supernumerary ribs were seen in rats with RAL exposures that were threefold higher than the exposure seen in humans who received the recommended daily dose.1

Placental and Breast Milk Passage

Placental transfer of RAL was demonstrated in both rats and rabbits. In pregnant rats given a dose of RAL 600 mg/kg per day, mean fetal blood concentrations were approximately 1.5-fold to 2.5-fold higher than the concentrations in maternal plasma at 1 hour and 24 hours postdose, respectively. However, in rabbits, the mean drug concentration in fetal plasma was approximately 2% of the mean maternal plasma concentration at both 1 hour and 24 hours after a maternal dose of 1,000 mg/kg per day.1

RAL is secreted in the milk of lactating rats. At a maternal dose of RAL 600 mg/kg per day, the mean drug concentration in milk was about threefold higher than the mean drug concentration in maternal plasma. No effects in rat offspring were attributable to RAL exposure through breast milk.1

Human Studies in Pregnancy

Pharmacokinetics

RAL pharmacokinetics (PKs) were evaluated in 42 pregnant women in the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) P1026s study, a Phase IV prospective PK study of selected antiretroviral (ARV) drugs during pregnancy and postpartum. RAL PKs in pregnant women showed extensive variability that was similar to the variability seen in nonpregnant women. Median RAL area under the curve (AUC) was reduced by approximately 50% during pregnancy. No significant difference was seen between third-trimester trough concentrations and postpartum trough concentrations. Plasma HIV RNA levels were <400 copies/mL in 92% of women at delivery. Given the high rates of virologic suppression and the lack of a clear relationship between RAL concentration and virologic effect in nonpregnant adults, no change in dosing was recommended during pregnancy.2 In a study of 22 women with paired third-trimester and postpartum data from the Pharmacokinetics of newly developed Antiretroviral agents in HIV-infected pregnant women (PANNA) Network, a network of European centers that collect PK data in pregnant women with HIV, the geometric mean ratios (GMRs) of third-trimester/postpartum values were 0.71 for AUC from 0 to 12 hours (AUC0–12h) (90% confidence interval [CI] 0.53–0.96), 0.82 for maximum concentration (Cmax) (range 0.55–1.253), and 0.64 for concentration 12 hours after dose (C12h) (range 0.34–1.22). One patient was below the target C12h in the third trimester, and no patients were below the threshold postpartum. No change in dosing during pregnancy was recommended based on these data.3 In a single-center, observational study of pregnant women who were started on RAL as part of intensification of an ARV regimen or as part of a triple-ARV regimen, the RAL C12h in the second and third trimester were similar to historical data in a nonpregnant population.4

A population PK model of once-daily 1,200-mg RAL pooled 11 PK studies (n = 221) with the primary target for efficacy set as the lower bound of the 90% confidence interval (CI) of the trough concentration >0.75. The simulated trough GMR for once-daily 1,200-mg RAL was 0.51 (CI=0.41–0.63), falling below the primary target for efficacy and supporting the current recommendation against daily RAL dosing in pregnancy.5

Caution is advised when RAL is coadministered with atazanavir, a uridine diphosphate glucuronosyltransferase A1 inhibitor, because this combination can result in elevated levels of RAL in nonpregnant adults with no medical conditions.6

Placental and Breast Milk Passage

An ex vivo study of term placentas from normal pregnancies reported high bidirectional transfer of RAL across the placenta.7

In vivo human studies have confirmed that RAL readily crosses the placenta. In the IMPAACT P1026s study, the ratio of cord blood-to-maternal-plasma RAL concentrations was 1.5.2 In the P1097 study, the median ratio of cord blood-to-maternal-delivery plasma RAL concentrations was 1.48 (with a range of 0.32–4.33), and in the PANNA study it was 1.21.3,8 In the above-mentioned single-center, observational study of pregnant women who were started on RAL as part of intensification of an ARV regimen or as part of a triple-ARV regimen, the cord blood-to-maternal-plasma RAL concentration ratio was 1.03.4 Other case reports have shown cord blood-to-maternal-blood drug level ratios of 1.00 to 1.06.9-11 In three cases of preterm delivery at 29 to 33 weeks gestation (in two of these cases, RAL was added to the maternal ARV regimen shortly before anticipated preterm delivery), cord blood-to-maternal-plasma ratios ranged from 0.44 to 1.88.12

RAL secretion in human breast milk is largely unstudied. A single case study demonstrated low RAL transfer into breast milk and little accumulation.13

Teratogenicity/Adverse Pregnancy Outcomes

In a retrospective study of 703 women in the French Perinatal Cohort who received RAL during pregnancy, rates of birth defects among infants born to women who were on RAL at conception were slightly higher than those born to women who initiated RAL later in pregnancy (6.4% vs. 2.3%, P = 0.04). When compared with matched controls, RAL exposure at conception was not associated significantly with birth defects, and no specific pattern of birth defects emerged during the study. No differences in other perinatal outcomes between groups were observed.14 Merck reviewed data on 456 periconception exposures to RAL and found no instances of neural tube defects; this review included data from the Merck database, the Antiretroviral Pregnancy Registry, and the U.K./Ireland and French pregnancy cohorts.15

The IMPAACT P1081 study randomized 408 antiretroviral therapy-naive women in Africa, South America, Thailand, and the United States who presented late in pregnancy to receive RAL plus two nucleoside reverse transcriptase inhibitors (NRTIs) or efavirenz plus two NRTIs. Both regimens were well tolerated, with similar rates of stillbirth and preterm birth among women and similar rates of serious adverse events among women and infants; a significantly larger proportion of women on a RAL-containing regimen achieved a viral load less than 200 copies per mL at or near delivery.16 In multiple case reports and case series that involved 4, 5, and 14 pregnant women who were treated with RAL in combination with two or three other ARV drugs because of persistent viremia or late presentation, RAL was well tolerated and led to rapid reduction in HIV RNA levels.17-23

The Antiretroviral Pregnancy Registry has monitored sufficient numbers of first-trimester exposures to RAL to detect at least a twofold increase in the risk of overall birth defects, but no such increase has been observed. Among the cases of first-trimester RAL exposure that have been reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 3.1% (15 of 486 live births; 95% CI, 1.7%–5.0%), compared with a 2.7% total prevalence in the U.S. population, based on Centers for Disease Control and Prevention surveillance.24,25 Supplemental data from the Antiretroviral Pregnancy Registry about central nervous system birth defect outcomes among 824 live births with exposure to RAL during periconception (n = 327) or pregnancy (later first trimester n = 95; second or third trimester n = 399) reported one central nervous system birth defect with exposure to RAL in the late first trimester, but this was not a neural tube or encephalocele defect.24

Safety

In the P1026s study, the P1081 study, and the PANNA study, RAL was well tolerated, with no treatment-related serious adverse events observed in pregnant women.2,3,16 However, in one case report, 10-fold to 23-fold increases in maternal liver transaminase levels were reported after initiation of RAL. Resolution occurred when RAL was discontinued.26 Drug levels were not measured.

One case of drug reaction has been reported in a postpartum woman with eosinophilia and systemic symptoms syndrome with extensive pulmonary involvement. The drug reaction resolved with discontinuation of RAL. Such reactions have been reported in nonpregnant adults who were receiving RAL, and these reactions should be taken into consideration when making a differential diagnosis of fever in patients on RAL during pregnancy or the postpartum period.27 In a study of 155 nonpregnant adults with HIV (mean age 49.2 years) who initiated RAL-containing therapy, skeletal muscle toxicity occurred in 23.9% of participants, and isolated creatine kinase (CK) elevation was reported in 21.3% of participants. These instances of CK elevation were Grade 1 or 2 and self-limiting. Fewer than 3% of patients complained of myalgia or muscle weakness. Skeletal muscle toxicity and CK elevation were associated significantly with prior use of zidovudine, higher baseline CK levels, and a higher body mass index.28

Because RAL is highly protein bound to albumin, concern exists about displacement of bilirubin from albumin in the neonate, which potentially could increase the risk of neonatal hyperbilirubinemia. In an in vitro study, RAL had minimal effect on bilirubin–albumin binding at concentrations of 5 µM and 10 µM, caused a small but statistically significant increase in unbound bilirubin at 100 µM, and caused potentially harmful increases at 500 µM and 1,000 µM.29 These data suggest that the effect of RAL on neonatal bilirubin binding is unlikely to be clinically significant at the typical peak concentrations that are reached in adults who receive the recommended dose (adult concentrations with standard RAL doses had a geometric mean Cmax of 4.5 μM, a median Cmax of 6.5 μM, and a maximum observed Cmax of 10.2 μM).29 In the P1097 study, one of 19 infants (5.3%) received phototherapy for treatment of hyperbilirubinemia, but this was judged to be unrelated to maternal RAL use.8 In a retrospective study of 31 pregnant women who received a standard dose of RAL as part of a standard ARV regimen or as part of an intensification regimen late in pregnancy (at a median gestational age of 34 weeks), mild elevation of transaminase levels was reported in 35% of neonates.30

Excerpt from Table 11

Generic Name
(Abbreviation)
Trade Name
Formulation Dosing Recommendationsa Use in Pregnancy

Raltegravir
(RAL)
Isentress
Isentress HD

RAL (Isentress)

Film-Coated Tablets:

  • 400 mg

Chewable Tablets:

  • 25 mg
  • 100 mg

RAL (Isentress HD)

Film-Coated Tablets:

  • 600 mg

Standard Adult Doses

In Patients Who Are Not Receiving Rifampin:

  • RAL 400 mg, film-coated tablets twice daily without regard to food
  • Two RAL 600 mg, film-coated tablets (1,200 mg) once daily without regard to food for ARV-naive patients or patients who are already virologically suppressed on an initial regimen of RAL 400 mg twice daily
  • Chewable tablets and oral suspension doses are not interchangeable with either film-coated tablets or each other.

In Patients Who Are Receiving Rifampin:

  • Two RAL 400 mg, film-coated tablets (800 mg) twice daily without regard to food.

Pregnancy

PKs in Pregnancy:

  • Decreased drug concentrations in the third trimester are not of sufficient magnitude to warrant a change in dosing.

Dosing in Pregnancy:

  • No change in dose is indicated.
  • Once-daily dosing (i.e., two RAL 600 mg, film-coated tablets) should not be used in pregnant individuals until more information is available.

High placental transfer to fetus.b

No evidence of human teratogenicity (can rule out 1.5-fold increase in overall birth defects).

There is a case report of markedly elevated liver transaminases with RAL use in late pregnancy. Severe, potentially life-threatening, and fatal skin and HSRs have been reported in nonpregnant adults.

RAL chewable tablets contain phenylalanine.

To maximize RAL absorption, doses should not be administered within 2 hours of ingestion of any preparation containing minerals—such as iron or calcium—including prenatal vitamins.

a Individual ARV drug doses may need to be adjusted in patients with renal or hepatic insufficiency (for details, see the Adult and Adolescent Antiretroviral Guidelines, Appendix B, Table 11).

b Placental transfer categories are determined by mean or median cord blood/maternal delivery plasma drug ratio:

High: >0.6
Moderate: 0.3–0.6
Low: <0.3

Key: ARV = antiretroviral; HD = high dose; HSR = hypersensitivity reaction; PK = pharmacokinetic; RAL = raltegravir

References

  1. Raltegravir (Isentress) [package insert]. Food and Drug Administration. 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022145s042,203045s016,205786s008lblrpl.pdf.
  2. Watts DH, Stek A, Best BM, et al. Raltegravir pharmacokinetics during pregnancy. J Acquir Immune Defic Syndr. 2014;67(4):375-381. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25162818.
  3. Blonk M, Colbers A, Hidalgo-Tenorio C, et al. Raltegravir in HIV-1 infected pregnant women: pharmacokinetics, safety and efficacy. Clin Infect Dis. 2015;61(5):809-816. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25944344.
  4. Belissa E, Benchikh A, Charpentier C, et al. Raltegravir plasma concentrations on HIV-1 infected pregnant women. Presented at: Conference on Retroviruses and Opportunistic Infections (CROI); 2015. Seattle, WA.
  5. Bukkems VE, Post TM, Colbers AP, Burger DM, Svensson EM. A population pharmacokinetics analysis assessing the exposure of raltegravir once-daily 1200 mg in pregnant women living with HIV. CPT Pharmacometrics Syst Pharmacol. 2021;10(2):161-172. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33369217.
  6. Krishna R, East L, Larson P, et al. Atazanavir increases the plasma concentrations of 1200 mg raltegravir dose. Biopharm Drug Dispos. 2016;37(9):533-541. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27696440.
  7. Vinot C, Treluyer JM, Giraud C, Gavard L, Peytavin G, Mandelbrot L. Bidirectional transfer of raltegravir in an ex vivo human cotyledon perfusion model. Antimicrob Agents Chemother. 2016;60(5):3112-3114. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26833154.
  8. 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: http://www.ncbi.nlm.nih.gov/pubmed/25162819.
  9. Pinnetti C, Baroncelli S, Villani P, et al. Rapid HIV-RNA decline following addition of raltegravir and tenofovir to ongoing highly active antiretroviral therapy in a woman presenting with high-level HIV viraemia at week 38 of pregnancy. J Antimicrob Chemother. 2010;65(9):2050-2052. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20630894.
  10. Croci L, Trezzi M, Allegri MP, et al. Pharmacokinetic and safety of raltegravir in pregnancy. Eur J Clin Pharmacol. 2012;68(8):1231-1232. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22382989.
  11. McKeown DA, Rosenvinge M, Donaghy S, et al. High neonatal concentrations of raltegravir following transplacental transfer in HIV-1 positive pregnant women. AIDS. 2010;24(15):2416-2418. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20827058.
  12. Hegazi A, Mc Keown D, Doerholt K, Donaghy S, Sadiq ST, Hay P. Raltegravir in the prevention of mother-to-child transmission of HIV-1: effective transplacental transfer and delayed plasma clearance observed in preterm neonates. AIDS. 2012;26(18):2421-2423. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23151500.
  13. Feiterna-Sperling C, Bukkems VE, Teulen MJA, Colbers AP, network P. Low raltegravir transfer into the breastmilk of a woman living with HIV. AIDS. 2020;34(12):1863-1865. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32675580.
  14. Sibiude J, Le Chenadec J, Mandelbrot L, et al. Risk of birth defects and perinatal outcomes in HIV-infected women exposed to integrase strand inhibitors during pregnancy. AIDS. 2021;35(2):219-226. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33048878.
  15. Shamsuddin H, Raudenbush CL, Sciba BL, et al. Evaluation of neural tube defects (NTDs) after exposure to raltegravir During Pregnancy. J Acquir Immune Defic Syndr. 2019;81(3):247-250. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30908331.
  16. Joao EC, Morrison RL, Shapiro DE, et al. Raltegravir versus efavirenz in antiretroviral-naive pregnant women living with HIV (NICHD P1081): an open-label, randomised, controlled, phase 4 trial. Lancet HIV. 2020;7(5):e322-e331. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32386720.
  17. Taylor N, Touzeau V, Geit M, et al. Raltegravir in pregnancy: a case series presentation. Int J STD AIDS. 2011;22(6):358-360. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21680678.
  18. Cha A, Shaikh R, Williams S, Berkowitz LL. Rapid reduction in HIV viral load in late pregnancy with raltegravir: a case report. J Int Assoc Provid AIDS Care. 2013;12(5):312-314. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23695227.
  19. De Hoffer L, Di Biagio A, Bruzzone B, et al. Use of raltegravir in a late presenter HIV-1 woman in advanced gestational age: case report and literature review. J Chemother. 2013;25(3):181-183. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23783144.
  20. Westling K, Pettersson K, Kaldma A, Naver L. Rapid decline in HIV viral load when introducing raltegravir-containing antiretroviral treatment late in pregnancy. AIDS Patient Care STDS. 2012;26(12):714-717. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23101466.
  21. Nobrega I, Travassos AG, Haguihara T, Amorim F, Brites C. Short communication: use of raltegravir in late-presenting HIV-infected pregnant women. AIDS Res Hum Retroviruses. 2013;29(11):1451-1454. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23731224.
  22. Adeyemo A, Wood C, Govind A. Achieving rapid reduction of HIV-1 viral load in HIV-positive pregnant women close to term—an obstetric/medical emergency: a review of three cases. Int J STD AIDS. 2013;24(7):591-592. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23970779.
  23. Maliakkal A, Walmsley S, Tseng A. Critical review: review of the efficacy, safety, and pharmacokinetics of raltegravir in pregnancy. J Acquir Immune Defic Syndr. 2016;72(2):153-161. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27183177.
  24. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for 1 January 1989–31 January 2021. Wilmington, NC: Registry Coordinating Center; 2021. Available at: http://www.apregistry.com/.
  25. Sibiude J, Warszawski J, Blanchard S, et al. Evaluation of the risk of birth defects among children exposed to raltegravir in utero in the ANRS-French perinatal cohort EPF. Presented at: International AIDS Society; 2017. Paris, France.
  26. Renet S, Closon A, Brochet MS, Bussieres JF, Boucher M. Increase in transaminase levels following the use of raltegravir in a woman with a high HIV viral load at 35 weeks of pregnancy. J Obstet Gynaecol Can. 2013;35(1):68-72. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23343800.
  27. Yee BE, Nguyen NH, Lee D. Extensive pulmonary involvement with raltegravir-induced DRESS syndrome in a postpartum woman with HIV. BMJ Case Rep. 2014;2014:bcr2013201545. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24798353.
  28. Calza L, Danese I, Colangeli V, et al. Skeletal muscle toxicity in HIV-1-infected patients treated with a raltegravir-containing antiretroviral therapy: a cohort study. AIDS Res Hum Retroviruses. 2014;30(12):1162-1169. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25369244.
  29. Clarke DF, Wong RJ, Wenning L, Stephenson DK, Mirochnick M. Raltegravir in vitro effect on bilirubin binding. Pediatr Infect Dis J. 2013;32(9):978-980. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23470680.
  30. Cecchini DM, Martinez MG, Morganti LM, Rodriguez CG. Antiretroviral therapy containing raltegravir to prevent mother-to-child transmission of HIV in infected pregnant women. Infect Dis Rep. 2017;9(2):7017. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28663779.

Integrase Inhibitors

Raltegravir (Isentress, RAL)

Excerpt from Table 11

Generic Name
(Abbreviation)
Trade Name
Formulation Dosing Recommendationsa Use in Pregnancy

Raltegravir
(RAL)
Isentress
Isentress HD

RAL (Isentress)

Film-Coated Tablets:

  • 400 mg

Chewable Tablets:

  • 25 mg
  • 100 mg

RAL (Isentress HD)

Film-Coated Tablets:

  • 600 mg

Standard Adult Doses

In Patients Who Are Not Receiving Rifampin:

  • RAL 400 mg, film-coated tablets twice daily without regard to food
  • Two RAL 600 mg, film-coated tablets (1,200 mg) once daily without regard to food for ARV-naive patients or patients who are already virologically suppressed on an initial regimen of RAL 400 mg twice daily
  • Chewable tablets and oral suspension doses are not interchangeable with either film-coated tablets or each other.

In Patients Who Are Receiving Rifampin:

  • Two RAL 400 mg, film-coated tablets (800 mg) twice daily without regard to food.

Pregnancy

PKs in Pregnancy:

  • Decreased drug concentrations in the third trimester are not of sufficient magnitude to warrant a change in dosing.

Dosing in Pregnancy:

  • No change in dose is indicated.
  • Once-daily dosing (i.e., two RAL 600 mg, film-coated tablets) should not be used in pregnant individuals until more information is available.

High placental transfer to fetus.b

No evidence of human teratogenicity (can rule out 1.5-fold increase in overall birth defects).

There is a case report of markedly elevated liver transaminases with RAL use in late pregnancy. Severe, potentially life-threatening, and fatal skin and HSRs have been reported in nonpregnant adults.

RAL chewable tablets contain phenylalanine.

To maximize RAL absorption, doses should not be administered within 2 hours of ingestion of any preparation containing minerals—such as iron or calcium—including prenatal vitamins.

a Individual ARV drug doses may need to be adjusted in patients with renal or hepatic insufficiency (for details, see the Adult and Adolescent Antiretroviral Guidelines, Appendix B, Table 11).

b Placental transfer categories are determined by mean or median cord blood/maternal delivery plasma drug ratio:

High: >0.6
Moderate: 0.3–0.6
Low: <0.3

Key: ARV = antiretroviral; HD = high dose; HSR = hypersensitivity reaction; PK = pharmacokinetic; RAL = raltegravir

Download Guidelines