Isentress

Generic Name: Raltegravir Potassium
Class: Integrase Inhibitors
Chemical Name: N - [(4 - Fluorophenyl)methyl] - 1,6 - dihydro - 5 - hydroxy - 1 - methyl - 2 - {1 - methyl - 1 - [[(5 - methyl - 1,3,4 - oxadiazol - 2 - yl)carbonyl]amino]ethyl} - 6 - oxo - 4 - pyrimidinecarboxamide monopotassium salt
Molecular Formula: C₂₀H₂₀FKN₆O₅
CAS Number: 871038-72-1

Introduction

Antiretroviral; HIV integrase inhibitor.^{1 2 3 4 5}

Uses for Isentress

Treatment of HIV Infection

Treatment of HIV-1 infection in conjunction with other antiretrovirals.^{1 8 14}

Safety and efficacy not established in pediatric patients <16 years of age.^{1 13}

Isentress Dosage and Administration

Administration

Oral Administration

Administer orally¹ without regard to food.^{1 5}

Dosage

Available as raltegravir potassium; dosage expressed in terms of raltegravir.¹

If used with rifampin, dosage adjustment of raltegravir is necessary.¹

Must be given in conjunction with other antiretrovirals.¹

Pediatric Patients

Treatment of HIV Infection

Oral

Adolescents ≥16 years of age: 400 mg twice daily.¹

Adolescents ≥16 years of age receiving rifampin concomitantly 800 mg twice daily.¹

Adults

Treatment of HIV Infection

Oral

400 mg twice daily.^{1 5}

Adults receiving rifampin: 800 mg twice daily.¹

Special Populations

Hepatic Impairment

Dosage adjustment not necessary in patients with mild to moderate hepatic impairment;^{1 5} data not available in patients with severe hepatic impairment.¹ (See Hepatic Impairment under Cautions.)

Renal Impairment

Dosage adjustment not necessary.^{1 5} Avoid administering drug before dialysis session.¹ (See Renal Impairment under Cautions.)

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.¹

Cautions for Isentress

Contraindications

• 
  

  Manufacturer states none known.¹

  
  

Warnings/Precautions

Immune Reconstitution Syndrome

During initial treatment, patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jiroveci [formerly P. carinii], varicella-zoster virus [VZV]); this may necessitate further evaluation and treatment.¹

Interactions

Concomitant use with drugs that are potent inducers of uridine diphosphate-glucuronosyltransferase (UGT) 1A1 (e.g., rifampin) may result in decreased plasma concentrations of raltegravir.¹ (See Interactions and see Dosage and Administration.)

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., diffuse rash with fever, facial edema) reported.^{1 b}

Musculoskeletal Effects

Increased serum CK concentrations observed.¹

Myopathy and rhabdomyolysis reported rarely; relationship to drug not known.¹ Use caution in patients at increased risk of myopathy or rhabdomyolysis, including those receiving concomitant therapy with a drug associated with myopathy or rhabdomyolysis.¹

Specific Populations

Pregnancy

Category C.¹

Antiretroviral Pregnancy Registry at 800-258-4263.¹

Some experts state that safety and pharmacokinetic data are insufficient to recommend raltegravir in pregnant women.⁷

Lactation

Distributed into milk in rats; not known whether distributed into human milk.¹

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.^{1 5 7}

Pediatric Use

Safety and efficacy not established in pediatric patients <16 years of age.^{1 13}

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.¹

Use with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.¹

Hepatic Impairment

Risk for further elevations in hepatic enzyme concentrations in patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.¹ (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Not known if removed by dialysis; avoid administering drug before dialysis session.¹ (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Insomnia, headache, nausea, asthenia, fatigue.¹

Interactions for Isentress

Metabolized by UGT 1A1.¹ Does not inhibit UGT 1A1 or UGT 2B7 in vitro.¹

Not a substrate for CYP isoenzymes.¹ Does not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A or induce CYP1A2, 2B6, or 3A4.¹

Does not inhibit P-glycoprotein-mediated transport.¹

Drugs Affecting or Metabolized by Uridine Diphosphate-glucuronosyltransferase 1A1

Potential pharmacokinetic interactions with drugs that are potent inducers of UGT 1A1 (decreased plasma concentrations of raltegravir)^{1 5} or inhibitors of UGT 1A1 (increased plasma concentrations of raltegravir).¹

Not expected to affect pharmacokinetics of drugs that are substrates for UGT 1A1 or UGT 2B7.¹

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions unlikely with drugs that are substrates for CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A.¹

Drugs Metabolized by P-Glycoprotein Transport System

Pharmacokinetic interactions unlikely with drugs that are substrates for P-glycoprotein.¹

Specific Drugs

Drug	Interaction	Comments
Abacavir	In vitro evidence of additive to synergistic antiretroviral effects1
Amprenavir	In vitro evidence of additive to synergistic antiretroviral effects1
Anticonvulsants (phenobarbital, phenytoin)	Phenytoin and/or phenobarbital potentially may affect the UGT 1A1 pathway;11 effect on raltegravir pharmacokinetics unknown1	Concomitant use of phenytoin and/or phenobarbital prohibited in expanded-access program11
Antimycobacterials, rifamycins (rifabutin, rifampin, rifapentine)	Rifabutin: Possible decreased raltegravir concentrations5 Rifampin: Decreased peak plasma concentrations and AUC of raltegravir1 5 11	Rifabutin: Consider possibility of pharmacokinetic interaction if optimal virologic response not achieved5 Rifampin: Dosage adjustment needed of raltegravir; use raltegravir 800 mg twice daily1 Rifapentine: Concomitant use not recommended5
Atazanavir	Atazanavir or ritonavir-boosted atazanavir: Increased raltegravir concentrations;1 clinical importance unknown; however, combination of ritonavir-boosted atazanavir and raltegravir reportedly well tolerated1 11 In vitro evidence of additive to synergistic antiretroviral effects1	Ritonavir-boosted atazanavir: Dosage adjustment of raltegravir not needed1
Benzodiazepines (e.g., midazolam)	Raltegravir not expected to affect pharmacokinetics of midazolam 1 10
Delavirdine	In vitro evidence of additive to synergistic antiretroviral effects1
Didanosine	In vitro evidence of additive to synergistic antiretroviral effects1
Efavirenz	Decreased raltegravir concentrations;1 11 clinical importance unknown11 In vitro evidence of additive to synergistic antiretroviral effects1	Consider possibility of a pharmacokinetic interaction if optimal virologic response not achieved5
Enfuvirtide	In vitro evidence of additive to synergistic antiretroviral effects1
Etravirine	Decreased raltegravir concentrations; no change in etravirine concentrations. Clinical importance unknown1
Hormonal contraceptives	Raltegravir not expected to affect pharmacokinetics of hormonal contraceptives1
Indinavir	In vitro evidence of additive to synergistic antiretroviral effects1
Lamivudine	Raltegravir not observed to have a clinically meaningful effect on pharmacokinetics of lamivudine1 In vitro evidence of additive to synergistic antiretroviral effects1
Lopinavir	In vitro evidence of additive to synergistic antiretroviral effects1
Methadone	Raltegravir not expected to affect pharmacokinetics of methadone1
Nelfinavir	In vitro evidence of additive to synergistic antiretroviral effects1
Nevirapine	In vitro evidence of additive to synergistic antiretroviral effects1
Omeprazole	Increased raltegravir concentrations1	Dosage adjustment not necessary1
Ritonavir	Pharmacokinetic interaction with low-dose ritonavir unlikely11 In vitro evidence of additive to synergistic antiretroviral effects1	Consider possibility of drug interactions between raltegravir and other protease inhibitors (PIs) when low-dose ritonavir is used to boost PI concentrations11
Saquinavir	In vitro evidence of additive to synergistic antiretroviral effects1
Stavudine	In vitro evidence of additive to synergistic antiretroviral effects1
Tenofovir	Increased raltegravir concentrations; no change in concentrations of tenofovir1 In vitro evidence of additive to synergistic antiretroviral effects1
Tipranavir	Ritonavir-boosted tipranavir: Decreased raltegravir concentrations; however, no effect on efficacy of raltegravir observed in small study1	Ritonavir-boosted tipranavir: Dosage adjustment of raltegravir not needed1 Consider possibility of pharmacokinetic interaction if optimal virologic response not achieved5
Zidovudine	In vitro evidence of additive to synergistic antiretroviral effects1

Isentress Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability not established.¹

Following oral administration in the fasted state, peak plasma concentrations attained in approximately 3 hours.¹

Food

AUC increased by approximately 13% when administered with a moderate-fat meal compared with administration in the fasting state.¹

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.¹

Not known whether crosses the placenta.¹

Plasma Protein Binding

83%.¹

Elimination

Metabolism

Metabolized mainly by UGT 1A1-mediated glucuronidation in the liver.^{1 5}

Elimination Route

Excreted in feces (51%) and urine (32%).¹

Not known if removed by dialysis.¹

Half-life

9 hours.¹

Special Populations

Moderate hepatic impairment: No clinically important pharmacokinetic differences between patients with moderate hepatic impairment and healthy individuals observed.¹

Severe hepatic impairment: Pharmacokinetics not studied.¹

Severe renal impairment: No clinically important pharmacokinetic differences between patients with severe renal impairment and healthy individuals observed.¹

Pediatric patients: Pharmacokinetics not established.¹

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).¹

ActionsActions

• 
  

  Inhibits catalytic activity of HIV-1 integrase, an enzyme that integrates HIV DNA into the host cell genome.^{1 4}

  
  


• 
  

  Inhibition of integrase prevents propagation of viral infection.^{1 4}

  
  


• 
  

  Active against some strains of HIV-1 resistant to nucleoside reverse transcriptase inhibitors (NRTIs) and PIs.¹

  
  


• 
  

  Resistant HIV-1 strains have been produced in vitro and have emerged during raltegravir therapy.^{1 b}

  
  

Advice to Patients

• 
  

  Critical nature of compliance with HIV therapy.¹ Used in conjunction with other antiretrovirals; do not use for monotherapy.¹

  
  


• 
  

  Antiretroviral therapy is not a cure for HIV infection, and opportunistic infections still may occur.¹ HIV transmission via sexual contact or sharing needles is not prevented by antiretrovirals.¹

  
  


• 
  

  Importance of reading patient information provided by the manufacturer.¹

  
  


• 
  

  Importance of informing clinician if unusual symptoms (e.g., muscle pain, tenderness, weakness) develop or known symptoms persist or worsen.¹

  
  


• 
  

  If a dose is missed, administer as soon as it is remembered; however, if a dose is skipped, a double dose should not be taken to make up for the missed dose.¹

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal products, and any concomitant illnesses (e.g., chronic HBV or HCV).¹

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

  
  


• 
  

  Importance of advising patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Raltegravir Potassium

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablet, film-coated	400 mg (of raltegravir)	Isentress	Merck

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Isentress 400MG Tablets (MERCK SHARP & DOHME): 60/$994.9 or 180/$2874.45

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions November 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Merck. Isentress (raltegravir) tablets prescribing information. Whitehouse Station, NJ; 2009 Jul.

2. Cooper D, Gatell J, Rockstroh J et al. Results of BENCHMRK-1, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA. 2007 Feb 25-28. Abstract 105aLB. From website.

3. Steigbigel R, Kumar P, Eron J et al. Results of BENCHMRK-2, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA. 2007 Feb 25-28. Abstract 105bLB. From website.

4. Grinsztejn B, Nguyen BY, Katlama C et al for Protocol 005 team. 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. 2007; 369:1261-9. [PubMed 17434401]

5. Panel on Antiretroviral Guidelines for Adults and Adolescents of the Department of Health and Human Services (DHHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (November 3, 2008). From the US Department of Health and Human Services HIV/AIDS Information Services (AIDSinfo) website.

6. Hammer SM, Saag MS, Schechter M et al. Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society–USA panel. JAMA. 2006; 296:827-43. [PubMed 16905788]

7. Perinatal HIV Guidelines Working Group. Public Health Service task force recommendations for use of antiretroviral drugs in pregnant HIV-infected women for maternal health and interventions to reduce perinatal HIV-1 transmission in the United States (April 29, 2009). From the US Department of Health and Human Services HIV/AIDS Information Services (AIDSinfo) website.

8. Markowitz M, Nguyen BY, Gotuzzo E 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. 2007; 46:125-33. [PubMed 17721395]

9. Anon. Two new drugs for HIV infection. Med Lett Drugs Ther. 2008; 50:2-4.

10. Iwamoto M, Kassahun K, Troyer MD et al. Lack of a pharmacokinetic effect of raltegravir on midazolam: in vitro/in vivo correlation. J Clin Pharmacol. 2008; 48:209-14. [PubMed 18077730]

11. Correll T, Klibanov OM. Integrase inhibitors: a new treatment option for patients with human immunodeficiency virus infection. Pharmacotherapy. 2008: 28:90-101.

12. Merck, North Wales, Pa. Personal communication.

13. Working Group on Antiretroviral Therapy and Medical Management of HIV-infected Children of the National Resource Center at the François-Xavier Bagnoud Center, Health Resources and Services Administration (HRSA), and National Institutes of Health (NIH). Guidelines for the use of antiretroviral agents in pediatric HIV infection (February 23, 2009). From the US Department of Health and Human Services HIV/AIDS Information Services (AIDSinfo) website.

14. Steigbigel RT, Cooper DA, Kumar PN et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med. 2008; 359:339-54. [PubMed 18650512]

b. Merck, North Wales, PA: Personal communication.

More Isentress resources

• Isentress Side Effects (in more detail)
• Isentress Use in Pregnancy & Breastfeeding
• Drug Images
• Isentress Drug Interactions
• Isentress Support Group
• 5 Reviews for Isentress - Add your own review/rating

• Isentress Prescribing Information (FDA)


• Isentress Consumer Overview


• Isentress Advanced Consumer (Micromedex) - Includes Dosage Information


• Isentress MedFacts Consumer Leaflet (Wolters Kluwer)


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