Isentress

Name: Isentress

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What is raltegravir, and how does it work (mechanism of action)?

  • Raltegravir (Isentress) is an antiretroviral medicine approved for the treatment of human immunodeficiency virus (HIV) infection. Raltegravir is an integrase inhibitor similar to elvitegravir (Vitekta) and dolutegravir (Tivicay). Raltegravir slows the spread of HIV infection by blocking the HIV integrase enzyme required for virus multiplication. To improve the chance of fighting HIV-1 infection, raltegravir must be taken with other HIV medicines. Although raltegravir does not cure HIV or AIDS, continuous HIV treatment with raltegravir can help patients control the infection and decrease their risk of acquiring HIV-related illnesses. Raltegravir helps to improve the immune system by increasing the number of white blood cells called CD4+ (T) cells, and consequently reduce the risk of death or getting opportunistic infections that can happen when the immune system is weak.
  • Raltegravir was initially approved by the FDA in October 2007.

Is raltegravir safe to take if I'm pregnant or breastfeeding?

  • Use of raltegravir in pregnant women has not been adequately evaluated. Due to the lack of conclusive safety data, raltegravir should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Raltegravir is classified as FDA pregnancy risk category C.
  • Breastfeeding is not recommended while taking raltegravir. To avoid transmitting the HIV-1 virus to the nursing infant, it is not recommended that HIV-1-infected mothers breastfeed their infants. It is not known if raltegravir is excreted into human milk.

What else should I know about raltegravir?

What preparations of raltegravir are available?
  • Film coated oral tablets: 400 mg
  • Chewable oral tablets: 25 mg and 100 mg
  • Granules for oral suspension: single use packet of 100 mg

How should I keep raltegravir stored?
  • Raltegravir should be stored at room temperature between 20 C to 25 C (68 F to 77 F).
  • For best protection the chewable tablets and granules for oral suspension should be stored in the original container.

Uses of Isentress

Isentress is an anti-HIV (antiretroviral) medicine used for the treatment of human immunodeficiency virus (HIV), the virus that causes AIDS (Acquired Immune Deficiency Syndrome). Isentress is used along with other anti-HIV medicines. Isentress will NOT cure HIV infection, however.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Introduction

Antiretroviral; HIV integrase strand transfer inhibitor (INSTI).1 200

Isentress Dosage and Administration

Administration

Oral Administration

Raltegravir (Isentress): Administer orally twice daily without regard to food.1 Use in conjunction with other antiretrovirals.1

Lamivudine/raltegravir (Dutrebis): Administer orally twice daily without regard to food.241 Use in conjunction with other antiretrovirals.241

Because antiretrovirals in lamivudine/raltegravir may also be available in single-entity or other fixed-combination preparations, take care to ensure that therapy is not duplicated when the fixed combination used in conjunction with other antiretrovirals.241 (See Precautions Related to Use of Fixed Combinations under Cautions.)

Chewable Tablets

Raltegravir (Isentress): May be chewed or swallowed whole.1 If needed, 100-mg chewable tablet can be divided into equal halves.1

Used in pediatric patients weighing ≥11 kg to <25 kg.1 Also may be used as alternative in pediatric patients weighing ≥25 kg who cannot swallow film-coated tablets.1

Film-coated Tablets

Raltegravir (Isentress): Must be swallowed whole.1 Used in adults, adolescents, and pediatric patients weighing ≥25 kg.1

Lamivudine/raltegravir (Dutrebis): Used in adults, adolescents, and pediatric patients ≥6 years of age weighing ≥30 kg.241

Oral Suspension

Raltegravir (Isentress): Immediately prior to use, contents of a single-use packet of powder for oral suspension must be mixed in 5 mL of water to provide a suspension containing 20 mg/mL.1 Appropriate dosage of the suspension is then administered orally using dosing syringe provided by the manufacturer.1

To prepare oral suspension, use dosing syringe provided by the manufacturer to measure and add 5 mL of water to the mixing cup provided by the manufacturer.1 Open a single-dose packet of powder for oral suspension and pour entire contents into the mixing cup, tightly close mixing cup, and gently swirl for 30–60 seconds.1 Suspension will appear cloudy.1

Draw recommended dosage of oral suspension into the dosing syringe and administer orally.1

Administer within 30 minutes of mixing; discard any remaining suspension.1 After each use, handwash dosing syringe and mixing cup with warm water and dish soap, rinse with water, and air dry.1

Used in pediatric patients ≥4 weeks of age weighing ≥3 kg to <20 kg.1

Dosage

Available as raltegravir potassium; dosage expressed in terms of raltegravir.1 241

Single-entity raltegravir (Isentress) chewable tablets and oral suspension are not bioequivalent to single-entity raltegravir film-coated tablets;1 do not substitute chewable tablets or oral suspension for the 400-mg film-coated tablet.1

Lamivudine/raltegravir (Dutrebis): A film-coated tablet containing lamivudine 150 mg and raltegravir 300 mg provides lamivudine and raltegravir exposures comparable to those attained when a 150-mg lamivudine tablet is administered concomitantly with a 400-mg raltegravir tablet.241

Bioavailability of raltegravir contained in lamivudine/raltegravir is higher than that of raltegravir contained in single-entity raltegravir;241 the 300-mg raltegravir dose in lamivudine/raltegravir provides raltegravir exposures comparable to those provided by a 400-mg dose of single-entity raltegravir.241

Pediatric Patients

Treatment of HIV Infection Oral

Raltegravir (Isentress) in infants and children ≥4 weeks of age weighing ≥3 kg to <20 kg (oral suspension): Dosage based on weight (approximately 6 mg/kg twice daily; up to 100 mg twice daily).1 (See Table 1.)

Raltegravir in pediatric patients weighing ≥11 kg to <25 kg (chewable tablets): Dosage based on weight (approximately 6 mg/kg twice daily; up to 300 mg twice daily).1 (See Table 1.)

Table 1. Dosage of Raltegravir (Isentress Oral Suspension or Chewable Tablets) in Pediatric Patients 4 Weeks of Age or Older Weighing at Least 3 kg to Less Than 25 kg

Body Weight (kg)

Dosage of Oral Suspension Containing 20 mg/mL

Dosage of Chewable Tablets

3 to <4

20 mg (1 mL) twice daily

Do not use

4 to <6

30 mg (1.5 mL) twice daily

Do not use

6 to <8

40 mg (2 mL) twice daily

Do not use

8 to <11

60 mg (3 mL) twice daily

Do not use

11 to <14

80 mg (4 mL) twice daily

75 mg twice daily (three 25-mg tablets twice daily)

14 to <20

100 mg (5 mL) twice daily

100 mg twice daily (one 100-mg tablet twice daily)

20 to <25

Do not use

150 mg twice daily (one and one-half 100-mg tablets twice daily)

Raltegravir in children and adolescents weighing ≥25 kg (film-coated tablets): 400 mg twice daily (one 400-mg film-coated tablet twice daily).1

Raltegravir in children and adolescents weighing ≥25 kg (chewable tablets): Dosage based on weight (approximately 6 mg/kg twice daily; up to 300 mg twice daily).1 (See Table 2.) Used as alternative in those who cannot swallow film-coated tablets.1

Table 2. Alternative Dosage of Raltegravir (Isentress Chewable Tablets) in Pediatric Patients Weighing ≥25 kg and Unable to Swallow Film-coated Tablets

Body Weight (kg)

Dosage

Number of Chewable Tablets

25 to <28

150 mg twice daily

One and one-half 100-mg tablets twice daily

28 to <40

200 mg twice daily

Two 100-mg tablets twice daily

≥40

300 mg twice daily

Three 100-mg tablets twice daily

Lamivudine/raltegravir (Dutrebis) in children ≥6 years of age weighing ≥30 kg (film-coated tablets): 1 tablet (lamivudine 150 mg and raltegravir 300 mg) twice daily.241

Lamivudine/raltegravir in adolescents ≥16 years of age (film-coated tablets): 1 tablet (lamivudine 150 mg and raltegravir 300 mg) twice daily.241

Adults

Treatment of HIV Infection Oral

Raltegravir (Isentress) film-coated tablets: 400 mg twice daily (one 400-mg film-coated tablet twice daily).1

Lamivudine/raltegravir (Dutrebis) film-coated tablets: 1 tablet (lamivudine 150 mg and raltegravir 300 mg) twice daily.241

Postexposure Prophylaxis following Occupational Exposure to HIV (PEP)† Oral

Raltegravir (Isentress): 400 mg twice daily.199 Used in conjunction with 2 NRTIs (see Postexposure Prophylaxis following Occupational Exposure to HIV [PEP] under Uses).199

Initiate PEP as soon as possible following exposure to HIV (preferably within hours); continue for 4 weeks, if tolerated.199

Postexposure Prophylaxis following Nonoccupational Exposure to HIV (nPEP)† Oral

Raltegravir 400 mg twice daily.198 Use in conjunction with 2 NRTIs (see Postexposure Prophylaxis following Nonoccupational Exposure to HIV [nPEP] under Uses).198

Initiate nPEP as soon as possible (within 72 hours) following nonoccupational exposure that represents a substantial risk for HIV transmission and continue for 28 days.198

nPEP not recommended if exposed individual seeks care ≥72 hours after exposure.198

Prescribing Limits

Pediatric Patients

Treatment of HIV Infection Pediatric Patients ≥4 Weeks of Age Weighing ≥3 kg to < 20 kg Oral

Raltegravir (Isentress) oral suspension: Maximum 100 mg twice daily.1

Pediatric Patients Weighing ≥11 kg Oral

Raltegravir (Isentress) chewable tablets: Maximum 300 mg twice daily.1

Pediatric Patients ≥6 Years of Age Weighing ≥30 kg Oral

Lamivudine/raltegravir (Dutrebis) film-coated tablets: Maximum 1 tablet (lamivudine 150 mg and raltegravir 300 mg) twice daily.241

Adults

Oral

Lamivudine/raltegravir (Dutrebis) film-coated tablets: Maximum 1 tablet (lamivudine 150 mg and raltegravir 300 mg) twice daily.241

Special Populations

Hepatic Impairment

Raltegravir (Isentress): Dosage adjustments not needed in patients with mild to moderate hepatic impairment;1 200 not studied in those with severe hepatic impairment.1

Lamivudine/raltegravir (Dutrebis): Dosage adjustments not needed in patients with mild to moderate hepatic impairment.241 Safety and efficacy not established in those with decompensated liver disease.241 (See Hepatic Impairment under Cautions.)

Renal Impairment

Raltegravir (Isentress): Dosage adjustments not needed in patients with renal impairment.1 200 Avoid administering raltegravir before dialysis session.1 (See Renal Impairment under Cautions.)

Lamivudine/raltegravir (Dutrebis): Do not use in patients with Clcr <50 mL/minute since reduction in lamivudine dosage needed in such patients.241 (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 (See Geriatric Use under Cautions.)

Interactions for Isentress

Raltegravir is metabolized by UGT1A1.1 Does not inhibit UGT1A1 or 2B7 in vitro.1

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

Does not inhibit P-glycoprotein-mediated transport.1

The following drug interactions are based on studies using raltegravir and a study using lamivudine/raltegravir.241 When lamivudine/raltegravir used, consider interactions associated with both drugs in the fixed combination.241

Drugs Affecting or Metabolized by UGT

Raltegravir and lamivudine/raltegravir: Potential pharmacokinetic interactions with drugs that are potent inducers of UGT1A1 (decreased plasma concentrations of raltegravir)1 241 or inhibitors of UGT1A1 (increased plasma concentrations of raltegravir).1 241

Raltegravir and lamivudine/raltegravir: Not expected to affect pharmacokinetics of drugs that are substrates for UGT1A1 or 2B7.1 241

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

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

Lamivudine/raltegravir: Not expected to affect pharmacokinetics of drugs metabolized by CYP isoenzymes.241

Drugs Affected by P-glycoprotein Transport

Raltegravir: Pharmacokinetic interactions unlikely with drugs that are substrates for P-glycoprotein (P-gp).1

Lamivudine/raltegravir: Not expected to affect pharmacokinetics of drugs that are P-gp substrates.241

Specific Drugs

Drug

Interaction

Comments

Abacavir

In vitro evidence of additive to synergistic antiretroviral effects1

Antacids, aluminum-, calcium-, or magnesium-containing

Aluminum- and/or magnesium-containing antacids: Decreased raltegravir concentrations and AUC1 200 241

Calcium-containing antacids: Decreased raltegravir concentrations and AUC;1 200 241 not considered clinically important1 200 241

Aluminum- and/or magnesium-containing antacids: Do not use in patients receiving raltegravir or lamivudine/raltegravir;1 200 241 use alternative acid-reducing agent200

Calcium-containing antacids: Dosage adjustments not needed if used with raltegravir or lamivudine/raltegravir1 200 241

Anticonvulsants (phenobarbital, phenytoin)

Phenytoin and/or phenobarbital: Potentially may affect UGT1A1 pathway;11 effect on raltegravir pharmacokinetics unknown1

Concomitant use of phenytoin and/or phenobarbital was prohibited in expanded-access program due to potential effect on UGT1A1 pathway11

Antifungals, azoles

Raltegravir and lamivudine/raltegravir: Clinically important effects on pharmacokinetics of azole antifungal unlikely1 241

Antimycobacterials, rifamycins (rifabutin, rifampin, rifapentine)

Rifabutin: Increased raltegravir AUC200

Rifampin: Decreased raltegravir concentrations and AUC1 11 200 241

Rifapentine: Altered raltegravir concentrations;200 once-daily rifapentine decreases raltegravir concentrations;200 once-weekly rifapentine decreases raltegravir concentrations but increases raltegravir AUC200

Rifabutin: Experts state dosage adjustments not needed if used with raltegravir200

Rifampin: In adults, increase dosage of raltegravir film-coated tablets to 800 mg twice daily1 200 and monitor closely for virologic response or consider use of rifabutin instead;200 data insufficient to make dosage recommendations for concomitant use in children and adolescents <18 years of age;1 do not use lamivudine/raltegravir concomitantly with rifampin;241 if concomitant use necessary, switch to single-entity components to allow adjustment of raltegravir dosage241

Rifapentine: Dosage adjustments not needed if once-weekly rifapentine used with raltegravir;200 do not use once-daily rifapentine with raltegravir200

Atazanavir

Ritonavir-boosted or unboosted atazanavir: Increased raltegravir concentrations and AUC;1 200 not considered clinically important1

Cobicistat-boosted atazanavir: Data not available200

Lamivudine/raltegravir: Clinically important effects on pharmacokinetics of PIs unlikely241

In vitro evidence of additive to synergistic antiretroviral effects1

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Dosage adjustments not needed if used concomitantly with raltegravir or lamivudine/raltegravir1 200 241

Benzodiazepines (e.g., midazolam)

Raltegravir: No clinically important effects on midazolam pharmacokinetics1 10

Buprenorphine

Raltegravir: No clinically important effect on pharmacokinetics of sublingual buprenorphine;200 clinically important effect on pharmacokinetics of buprenorphine subdermal implant not expected200

Lamivudine/raltegravir: Clinically important effects on pharmacokinetics of opiate analgesics unlikely241

Dosage adjustments not needed200

Citalopram

No clinically important pharmacokinetic interactions with raltegravir200

Dosage adjustments not needed if used with raltegravir200

Daclatasvir

Data not available200

Experts state dosage adjustments not needed if used with raltegravir200

Dasabuvir

Fixed combination of ombitasvir, paritaprevir, and ritonavir (ombitasvir/paritaprevir/ritonavir) copackaged with dasabuvir: No clinically important interactions with raltegravir180 200

Dasabuvir with ombitasvir/paritaprevir/ritonavir: Dosage adjustments not needed175 180

Darunavir

Ritonavir-boosted darunavir: Decreased raltegravir AUC, but no clinically important effects on pharmacokinetics of ritonavir-boosted darunavir;1 200 not considered clinically important1

Cobicistat-boosted darunavir: Clinically important interactions not expected if used with raltegravir237

Lamivudine/raltegravir: Clinically important effects on pharmacokinetics of PIs unlikely241

Ritonavir-boosted or cobicistat-boosted darunavir: Dosage adjustments not needed if used with raltegravir or lamivudine/raltegravir1 200 241

Delavirdine

In vitro evidence of additive to synergistic antiretroviral effects1

Didanosine

In vitro evidence of additive to synergistic antiretroviral effects1

Dolutegravir

No in vitro evidence of antagonistic antiretroviral effects236

Efavirenz

Decreased raltegravir concentrations and AUC;1 11 200 not considered clinically important1

Lamivudine/raltegravir: Clinically important effects on pharmacokinetics of nonnucleoside reverse transcriptase inhibitors (NNRTIs) unlikely241

In vitro evidence of additive to synergistic antiretroviral effects1

Dosage adjustments not needed if used with raltegravir or lamivudine/raltegravir1 200 241

Elbasvir and grazoprevir

Elbasvir: No clinically important pharmacokinetic interactions with raltegravir177 200

Grazoprevir: Increased raltegravir concentrations and AUC;177 200 no effect on grazoprevir concentrations177 200

Fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir): Dosage adjustments not needed if used with raltegravir177 200

Elvitegravir

No in vitro evidence of antagonistic antiretroviral effects242

Enfuvirtide

In vitro evidence of additive to synergistic antiretroviral effects1

Etravirine

Decreased raltegravir concentrations and AUC, but no clinically important effect on etravirine pharmacokinetics;1 200 214 not considered clinically important1 200 214

Lamivudine/raltegravir: No clinically important effects on raltegravir exposures241

No in vitro evidence of antagonistic antiretroviral effects214

Dosage adjustments not needed if used concomitantly with raltegravir or lamivudine/raltegravir1 200 214 241

Estrogens/progestins

No clinically important effects on pharmacokinetics of hormonal contraceptives1 200

Dosage adjustments not needed if used with raltegravir or lamivudine/raltegravir200 241

Fosamprenavir

Fosamprenavir or ritonavir-boosted fosamprenavir: Decreased concentrations and AUCs of raltegravir and amprenavir (active metabolite of fosamprenavir)205

Lamivudine/raltegravir: Clinically important effects on pharmacokinetics of PIs unlikely241

In vitro evidence of additive to synergistic antiretroviral effects with amprenavir1

Fosamprenavir or ritonavir-boosted fosamprenavir: Appropriate dosages for concomitant use with respect to safety and efficacy not established;205 some experts state dosage adjustments not needed200

HMG-CoA reductase inhibitors (statins)

Raltegravir, lamivudine/raltegravir: Clinically important effects on pharmacokinetics of statins unlikely1 241

Indinavir

In vitro evidence of additive to synergistic antiretroviral effects1

Lamivudine

No clinically important effects on lamivudine pharmacokinetics1

In vitro evidence of additive to synergistic antiretroviral effects1

Dosage adjustments not needed if lamivudine used with raltegravir1

Ledipasvir and sofosbuvir

Ledipasvir: No clinically important effects on pharmacokinetics of raltegravir or ledipasvir181 200

Fixed combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir): Clinically important pharmacokinetic interactions with raltegravir not expected181 200

Ledipasvir/sofosbuvir: Dosage adjustments not needed if used with raltegravir200

Lopinavir/ritonavir

Decreased raltegravir concentrations;200 no change in lopinavir/ritonavir concentrations200

Lamivudine/raltegravir: Clinically important effects on pharmacokinetics of PIs unlikely241

In vitro evidence of additive to synergistic antiretroviral effects1

Dosage adjustments not needed200

Maraviroc

Decreased raltegravir concentrations and AUC and decreased maraviroc concentrations and AUC;200 224 not considered clinically important224

Recommended maraviroc dosage is 300 mg twice daily when used with raltegravir, provided regimen does not include a potent CYP3A inhibitor or inducer200 224

Methadone

Raltegravir: No clinically important effects on methadone pharmacokinetics1 200

Lamivudine/raltegravir: Clinically important effects on pharmacokinetics of opiate analgesics unlikely241

Dosage adjustments not needed if used with raltegravir or lamivudine/raltegravir1 200 241

Nelfinavir

Lamivudine/raltegravir: Clinically important effects on pharmacokinetics of PIs unlikely241

In vitro evidence of additive to synergistic antiretroviral effects1

Nevirapine

Lamivudine/raltegravir: Clinically important effects on pharmacokinetics of NNRTIs unlikely241

In vitro evidence of additive to synergistic antiretroviral effects1

Dosage adjustments not needed200

Ombitasvir

Ombitasvir/paritaprevir/ritonavir with or without dasabuvir: No clinically important interactions with raltegravir180 200

Ombitasvir/paritaprevir/ritonavir with or without dasabuvir: Dosage adjustments not needed if used with raltegravir175 179 180 200

Paritaprevir

Ombitasvir/paritaprevir/ritonavir with or without dasabuvir: No clinically important interactions with raltegravir180 200

Ombitasvir/paritaprevir/ritonavir with or without dasabuvir: Dosage adjustments not needed if used with raltegravir175 179 180 200

Phosphodiesterase (PDE) type 5 inhibitors

Lamivudine/raltegravir: Clinically important effects on pharmacokinetics of PDE type 5 inhibitors unlikely241

Proton-pump inhibitors (omeprazole)

Omeprazole: Substantially increased raltegravir concentrations and AUC;1 200 not considered clinically important1 200

Raltegravir and lamivudine/raltegravir not expected to have clinically important effects on pharmacokinetics of proton-pump inhibitors1 241

Proton-pump inhibitors (e.g., omeprazole): Dosage adjustments not needed if used with raltegravir or lamivudine/raltegravir1 200 241

Rilpivirine

Increased raltegravir concentrations;200 226 not considered clinically important200

Lamivudine/raltegravir: Clinically important effects on pharmacokinetics of NNRTIs unlikely241

No in vitro evidence of antagonistic antiretroviral effects226

Dosage adjustments not needed if used with raltegravir200 226

Ritonavir

Low-dose ritonavir: Decreased raltegravir peak concentrations and AUC1 200

Lamivudine/raltegravir: Clinically important effects on pharmacokinetics of PIs unlikely241

In vitro evidence of additive to synergistic antiretroviral effects1

Low-dose ritonavir: Dosage adjustments not needed;200 consider possibility of drug interactions between raltegravir and other HIV PIs when low-dose ritonavir is used to boost PI concentrations11

Saquinavir

Lamivudine/raltegravir: Clinically important effects on pharmacokinetics of PIs unlikely241

In vitro evidence of additive to synergistic antiretroviral effects1

Dosage adjustments not needed200

Simeprevir

No clinically important effects on pharmacokinetics of either drug187 200

Dosage adjustments not needed187 200

Sofosbuvir

Decreased raltegravir concentrations and AUC, but no effect on sofosbuvir pharmacokinetics;188 not considered clinically important188

Dosage adjustments not needed188

Sofosbuvir and velpatasvir

Fixed combination of sofosbuvir and velpatasvir (sofosbuvir/velpatasvir): No clinically important pharmacokinetic interactions with raltegravir176

Stavudine

In vitro evidence of additive to synergistic antiretroviral effects1

Tenofovir

Increased raltegravir concentrations and AUC, but no clinically important effects on tenofovir DF pharmacokinetics;1 200 not considered clinically important1

In vitro evidence of additive to synergistic antiretroviral effects1

Dosage adjustments not needed if used with raltegravir or lamivudine/raltegravir1 200 241

Tipranavir

Ritonavir-boosted tipranavir: Decreased raltegravir concentrations and AUC;1 200 not considered clinically important1

Lamivudine/raltegravir: Clinically important effects on pharmacokinetics of PIs not expected241

Ritonavir-boosted tipranavir: Dosage adjustments not needed if used with raltegravir or lamivudine/raltegravir1 200 241

Zidovudine

In vitro evidence of additive to synergistic antiretroviral effects1

Actions and Spectrum

  • Raltegravir is an HIV INSTI antiretroviral.1 200 Inhibits activity of HIV integrase, an enzyme that integrates HIV DNA into the host cell genome.4 1 Inhibition of integrase prevents propagation of viral infection.1 4

  • Active against HIV type 1 (HIV-1);1 200 also has some in vitro activity against HIV type 2 (HIV-2).1 200

  • HIV-1 resistant to raltegravir have been produced in vitro1 and have emerged during raltegravir therapy.1 17 18

  • Cross-resistance between raltegravir and other INSTIs (e.g., dolutegravir, elvitegravir) reported.19 20 21 22 23 235 242

Preparations

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

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Raltegravir Potassium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

For suspension

100 mg (of raltegravir) per packet

Isentress

Merck

Tablets, chewable

25 mg (of raltegravir)

Isentress

Merck

100 mg (of raltegravir)

Isentress

Merck

Tablets, film-coated

400 mg (of raltegravir)

Isentress

Merck

Raltegravir Potassium Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

300 mg (of raltegravir) with Lamivudine 150 mg

Dutrebis

Merck

Commonly used brand name(s)

In the U.S.

  • Isentress
  • Isentress HD

Available Dosage Forms:

  • Powder for Suspension
  • Tablet, Chewable
  • Tablet

Therapeutic Class: Antiretroviral Agent

Pharmacologic Class: Integrase Inhibitor

Dosage Forms and Strengths

  • Film-coated Tablets
    • 400 mg pink, oval-shaped, film-coated tablets with "227" on one side (Isentress).
    • 600 mg yellow, oval-shaped, film-coated tablets with Merck logo and "242" on one side and plain on the other side (Isentress HD).
  • Chewable Tablets
    • 100 mg pale orange, oval-shaped, orange-banana flavored, chewable tablets scored on both sides and imprinted on one face with the Merck logo and "477" on opposite sides of the score.
    • 25 mg pale yellow, round, orange-banana flavored, chewable tablets with the Merck logo on one side and "473" on the other side.
  • For Oral Suspension
    • 100 mg white to off-white, banana flavored, granular powder that may contain yellow or beige to tan particles in a child resistant single-use foil packet.

Clinical Studies

Description of Clinical Studies

The evidence of durable efficacy of Isentress 400 mg twice daily is based on the analyses of 240-week data from a randomized, double-blind, active-controlled trial, STARTMRK evaluating Isentress 400 mg twice daily in antiretroviral treatment-naïve HIV-1 infected adult subjects, the analysis of 48-week data from a randomized, double-blind, active-control trial, ONCEMRK evaluating Isentress HD 1200 mg (2 × 600 mg) once daily in treatment-naïve adult subjects, and 96-week data from 2 randomized, double-blind, placebo-controlled studies, BENCHMRK 1 and BENCHMRK 2, evaluating Isentress 400 mg twice daily in antiretroviral treatment-experienced HIV-1 infected adult subjects. See Table 16.

Table 16: Trials Conducted with Isentress and Isentress HD in Subjects with HIV-1 Infection
Trial Study Type Population Study Arms (N) Dose/Formulation Timepoint
STARTMRK Randomized, double-blind, active-controlled Treatment-Naïve Adults Isentress 400 mg Twice Daily (281)
Efavirenz 600 mg At Bedtime (282)
Both in combination with emtricitabine (+) tenofovir disoproxil fumarate
400 mg film-coated tablet Week 240
ONCEMRK Randomized, double-blind, active-controlled Treatment-Naïve Adults Isentress HD 1200 mg Once Daily (531) 600 mg film-coated tablet Week 48
Isentress 400 mg Twice Daily (266)
Both in combination with emtricitabine (+) tenofovir disoproxil fumarate
400 mg film-coated tablet
BENCHMRK 1 Randomized, double-blind, placebo-controlled Treatment-Experienced Adults Isentress 400 mg Twice Daily (232)
Placebo (118)
Both in combination with optimized background therapy
400 mg film-coated tablet Week 240 (Week 156 on double-blind plus Week 84 on open-label)
BENCHMRK 2 Randomized, double-blind, placebo-controlled Treatment-Experienced Adults Isentress 400 mg Twice Daily (230)
Placebo (119)
Both in combination with optimized background therapy
400 mg film-coated tablet Week 240 (Week 156 on double-blind plus Week 84 on open-label)

Treatment-Naïve Adult Subjects

STARTMRK (Isentress 400 mg twice daily)

STARTMRK is a Phase 3 randomized, international, double-blind, active-controlled trial to evaluate the safety and efficacy of Isentress 400 mg twice daily versus efavirenz 600 mg at bedtime both with emtricitabine (+) tenofovir disoproxil fumarate in treatment-naïve HIV-1-infected subjects with HIV-1 RNA >5000 copies/mL. Randomization was stratified by screening HIV-1 RNA level (≤50,000 copies/mL; or >50,000 copies/mL) and by hepatitis status. In STARTMRK, 563 subjects were randomized and received at least 1 dose of either raltegravir 400 mg twice daily or efavirenz 600 mg at bedtime, both in combination with emtricitabine (+) tenofovir disoproxil fumarate. There were 563 subjects included in the efficacy and safety analyses. At baseline, the median age of subjects was 37 years (range 19-71), 19% female, 58% non-white, 6% had hepatitis B and/or C virus co-infection, 20% were CDC Class C (AIDS), 53% had HIV-1 RNA greater than 100,000 copies per mL, and 47% had CD4+ cell count less than 200 cells per mm3; the frequencies of these baseline characteristics were similar between treatment groups.

ONCEMRK (Isentress HD 1200 mg [2 × 600 mg] once daily)

ONCEMRK is a Phase 3 randomized, international, double-blind, active-controlled trial to evaluate the safety and efficacy of Isentress HD 1200 mg (2 × 600 mg) once daily versus Isentress 400 mg twice daily, both in combination with emtricitabine (+) tenofovir disoproxil fumarate, in treatment-naïve HIV-1-infected subjects with HIV-1 RNA ≥1000 copies/mL. Randomization was stratified by screening HIV-1 RNA level (≤100,000 or >100,000 copies/mL) and by hepatitis B and C infection status.

In ONCEMRK, 797 subjects were randomized and received at least 1 dose of either raltegravir 1200 mg once daily or raltegravir 400 mg twice daily, both in combination with emtricitabine (+) tenofovir disoproxil fumarate. There were 797 subjects included in the efficacy and safety analyses. At baseline, the median age of subjects was 34 years (range 18-84), 15% female, 41% non-white, 3% had hepatitis B and/or C virus co-infection, 13% were CDC Class C (AIDS), 28% had HIV-1 RNA greater than 100,000 copies per mL, and 13% had CD4+ cell count less than 200 cells per mm3; the frequencies of these baseline characteristics were similar between treatment groups.

Table 17 shows the virologic outcomes in both studies. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing duration of follow-up.

Table 17: Virologic Outcomes of Randomized Treatment in STARTMRK and ONCEMRK (Snapshot Algorithm) in HIV Treatment-Naïve Adults
STARTMRK
Week 240
ONCEMRK
Week 48
Isentress
400 mg Twice Daily
(N=281)
Efavirenz
600 mg At Bedtime
(N=282)
Isentress HD
1200 mg Once Daily
(N=531)
Isentress
400 mg Twice Daily
(N=266)
Notes: Isentress BID, Isentress HD and Efavirenz were administered with emtricitabine (+) tenofovir disoproxil fumarate
* Lower Limit of Quantitation: STARTMRK <50 copies/mL; ONCEMRK < 40 copies/mL. † Includes subjects who discontinued because of adverse event (AE) or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window. ‡ Other Reasons includes: lost to follow-up, moved, non-compliance with study drug, physician decision, pregnancy, withdrawal by subject.
HIV RNA < Lower Limit of Quantitation* 66% 60% 89% 88%
  Treatment Difference 6.6% (95% CI: -1.4%, 14.5%) 0.5% (95% CI: -4.2%, 5.2%)
HIV RNA ≥ Lower Limit of Quantitation 8% 15% 5% 6%
No Virologic Data at Analysis Timepoint 26% 26% 6% 6%
  Reasons
    Discontinued trial due to AE or Death† 5% 10% 1% 2%
    Discontinued trial for Other Reasons‡ 15% 14% 4% 3%
    On trial but missing data at timepoint 6% 2% 1% 1%

In the ONCEMRK trial, Isentress HD 1200 mg (2 × 600 mg) once daily demonstrated consistent virologic and immunologic efficacy relative to Isentress 400 mg twice daily, both in combination with emtricitabine (+) tenofovir disoproxil fumarate, across demographic and baseline prognostic factors, including: baseline HIV RNA levels >100,000 copies/mL and demographic groups (including age, gender, race, ethnicity and region), concomitant proton pump inhibitors/H2 blockers use and viral subtypes (comparing non-clade B as a group to clade B).

Consistent efficacy in subjects receiving Isentress HD 1200 mg (2 × 600 mg) once daily was observed across HIV subtypes with 88.4% (296/335) and 90.2% (175/194) of subjects with B and non-B subtypes respectively, achieving HIV RNA <40 copies/mL at week 48 (Snapshot approach).

Treatment-Experienced Adult Subjects

BENCHMRK 1 and BENCHMRK 2 are Phase 3 studies to evaluate the safety and antiretroviral activity of Isentress 400 mg twice daily in combination with an optimized background therapy (OBT), versus OBT alone, in HIV-1-infected subjects, 16 years or older, with documented resistance to at least 1 drug in each of 3 classes (NNRTIs, NRTIs, PIs) of antiretroviral therapies. Randomization was stratified by degree of resistance to PI (1PI vs. >1PI) and the use of enfuvirtide in the OBT. Prior to randomization, OBT was selected by the investigator based on genotypic/phenotypic resistance testing and prior ART history.

Table 18 shows the demographic characteristics of subjects in the group receiving Isentress 400 mg twice daily and subjects in the placebo group.

Table 18: Trials BENCHMRK 1 and BENCHMRK 2 Baseline Characteristics
Randomized Studies
BENCHMRK 1 and BENCHMRK 2
Isentress 400 mg Twice Daily + OBT
(N = 462)
Placebo + OBT
(N = 237)
* Hepatitis B virus surface antigen positive or hepatitis C virus antibody positive.
Gender
Male 88% 89%
Female 12% 11%
Race
White 65% 73%
Black 14% 11%
Asian 3% 3%
Hispanic 11% 8%
Others 6% 5%
Age (years)
Median (min, max) 45 (16 to 74) 45 (17 to 70)
CD4+ Cell Count
Median (min, max), cells/mm3 119 (1 to 792) 123 (0 to 759)
≤50 cells/mm3 32% 33%
>50 and ≤200 cells/mm3 37% 36%
Plasma HIV-1 RNA
Median (min, max), log10 copies/mL 4.8 (2 to 6) 4.7 (2 to 6)
>100,000 copies/mL 36% 33%
History of AIDS
Yes 92% 91%
Prior Use of ART, Median (1st Quartile, 3rd Quartile)
Years of ART Use 10 (7 to 12) 10 (8 to 12)
Number of ART 12 (9 to 15) 12 (9 to 14)
Hepatitis Co-infection*
No Hepatitis B or C virus 83% 84%
Hepatitis B virus only 8% 3%
Hepatitis C virus only 8% 12%
Co-infection of Hepatitis B and C virus 1% 1%
Stratum
Enfuvirtide in OBT 38% 38%
Resistant to ≥2 PI 97% 95%

Table 19 compares the characteristics of optimized background therapy at baseline in the group receiving Isentress 400 mg twice daily and subjects in the control group.

Table 19: Trials BENCHMRK 1 and BENCHMRK 2 Characteristics of Optimized Background Therapy at Baseline
Randomized Studies
BENCHMRK 1 and BENCHMRK 2
Isentress 400 mg Twice Daily + OBT
(N = 462)
Placebo + OBT
(N = 237)
* Darunavir use in OBT in darunavir-naïve subjects was counted as one active PI. † The Phenotypic Sensitivity Score (PSS) and the Genotypic Sensitivity Score (GSS) were defined as the total oral ARTs in OBT to which a subject's viral isolate showed phenotypic sensitivity and genotypic sensitivity, respectively, based upon phenotypic and genotypic resistance tests. Enfuvirtide use in OBT in enfuvirtide-naïve subjects was counted as one active drug in OBT in the GSS and PSS. Similarly, darunavir use in OBT in darunavir-naïve subjects was counted as one active drug in OBT.
Number of ARTs in OBT
Median (min, max) 4 (1 to 7) 4 (2 to 7)
Number of Active PI in OBT by Phenotypic Resistance Test*
0 36% 41%
1 or more 60% 58%
Phenotypic Sensitivity Score (PSS)†
0 15% 18%
1 31% 30%
2 31% 28%
3 or more 18% 20%
Genotypic Sensitivity Score (GSS)†
0 25% 27%
1 38% 40%
2 24% 21%
3 or more 11% 10%

Week 96 outcomes for the 699 subjects randomized and treated with the recommended dose of Isentress 400 mg twice daily or placebo in the pooled BENCHMRK 1 and 2 studies are shown in Table 20.

Table 20: Virologic Outcomes of Randomized Treatment of BENCHMRK 1 and BENCHMRK 2 Trials at 96 Weeks (Pooled Analysis)
Isentress 400 mg Twice Daily + OBT
(N = 462)
Placebo + OBT
(N = 237)
* Includes subjects who switched to open-label raltegravir after Week 16 due to the protocol-defined virologic failure, subjects who discontinued prior to Week 96 for lack of efficacy, subjects changed OBT due to lack of efficacy prior to Week 96, or subjects who were ≥50 copies in the 96 week window. † Includes subjects who discontinued due to AE or death at any time point from Day 1 through the Week 96 window if this resulted in no virologic data on treatment during the Week 96 window. ‡ Other includes: withdrew consent, loss to follow-up, moved etc., if the viral load at the time of discontinuation was <50 copies/mL.
Subjects with HIV-1 RNA less than 50 copies/mL 55% 27%
Virologic Failure* 35% 66%
No virologic data at Week 96 Window
Reasons
  Discontinued study due to AE or death† 3% 3%
  Discontinued study for other reasons‡ 4% 4%
  Missing data during window but on study 4% <1%

The mean changes in CD4 count from baseline were 118 cells/mm3 in the group receiving Isentress 400 mg twice daily and 47 cells/mm3 for the control group.

Treatment-emergent CDC Category C events occurred in 4% of the group receiving Isentress 400 mg twice daily and 5% of the control group.

Virologic responses at Week 96 by baseline genotypic and phenotypic sensitivity score are shown in Table 21.

Table 21: Virologic Response at 96 Week Window by Baseline Genotypic/Phenotypic Sensitivity Score
Percent with HIV-1 RNA <50 copies/mL At Week 96
n Isentress 400 mg Twice Daily + OBT
(N = 462)
n Placebo + OBT
(N = 237)
* The Phenotypic Sensitivity Score (PSS) and the Genotypic Sensitivity Score (GSS) were defined as the total oral ARTs in OBT to which a subject's viral isolate showed phenotypic sensitivity and genotypic sensitivity, respectively, based upon phenotypic and genotypic resistance tests. Enfuvirtide use in OBT in enfuvirtide-naïve subjects was counted as one active drug in OBT in the GSS and PSS. Similarly, darunavir use in OBT in darunavir-naïve subjects was counted as one active drug in OBT.
Phenotypic Sensitivity Score (PSS)*
0 67 43 43 5
1 144 58 71 23
2 142 61 66 32
3 or more 85 48 48 42
Genotypic Sensitivity Score (GSS)*
0 116 39 65 5
1 177 62 95 26
2 111 61 49 53
3 or more 51 49 23 35

Switch of Suppressed Subjects from Lopinavir (+) Ritonavir to Raltegravir

The SWITCHMRK 1 & 2 Phase 3 studies evaluated HIV-1 infected subjects receiving suppressive therapy (HIV-1 RNA <50 copies/mL on a stable regimen of lopinavir 200 mg (+) ritonavir 50 mg 2 tablets twice daily plus at least 2 nucleoside reverse transcriptase inhibitors for >3 months) and randomized them 1:1 to either continue lopinavir (+) ritonavir (n=174 and n=178, SWITCHMRK 1 & 2, respectively) or replace lopinavir (+) ritonavir with Isentress 400 mg twice daily (n=174 and n=176, respectively). The primary virology endpoint was the proportion of subjects with HIV-1 RNA less than 50 copies/mL at Week 24 with a prespecified non-inferiority margin of -12% for each study; and the frequency of adverse events up to 24 weeks.

Subjects with a prior history of virological failure were not excluded and the number of previous antiretroviral therapies was not limited.

These studies were terminated after the primary efficacy analysis at Week 24 because they each failed to demonstrate non-inferiority of switching to Isentress versus continuing on lopinavir (+) ritonavir. In the combined analysis of these studies at Week 24, suppression of HIV-1 RNA to less than 50 copies/mL was maintained in 82.3% of the Isentress group versus 90.3% of the lopinavir (+) ritonavir group. Clinical and laboratory adverse events occurred at similar frequencies in the treatment groups.

Pediatric Subjects

2 to 18 Years of Age

IMPAACT P1066 is a Phase I/II open label multicenter trial to evaluate the pharmacokinetic profile, safety, tolerability, and efficacy of raltegravir in HIV infected children. This study enrolled 126 treatment experienced children and adolescents 2 to 18 years of age. Subjects were stratified by age, enrolling adolescents first and then successively younger children. Subjects were enrolled into cohorts according to age and received the following formulations: Cohort I (12 to less than 18 years old), 400 mg film-coated tablet; Cohort IIa (6 to less than 12 years old), 400 mg film-coated tablet; Cohort IIb (6 to less than 12 years old), chewable tablet; Cohort III (2 to less than 6 years), chewable tablet. Raltegravir was administered with an optimized background regimen.

The initial dose finding stage included intensive pharmacokinetic evaluation. Dose selection was based upon achieving similar raltegravir plasma exposure and trough concentration as seen in adults, and acceptable short term safety. After dose selection, additional subjects were enrolled for evaluation of long term safety, tolerability and efficacy. Of the 126 subjects, 96 received the recommended dose of Isentress [see Dosage and Administration (2.3)].

These 96 subjects had a median age of 13 (range 2 to 18) years, were 51% Female, 34% Caucasian, and 59% Black. At baseline, mean plasma HIV-1 RNA was 4.3 log10 copies/mL, median CD4 cell count was 481 cells/mm3 (range: 0 – 2361) and median CD4% was 23.3% (range: 0 – 44). Overall, 8% had baseline plasma HIV-1 RNA >100,000 copies/mL and 59% had a CDC HIV clinical classification of category B or C. Most subjects had previously used at least one NNRTI (78%) or one PI (83%).

Ninety-three (97%) subjects 2 to 18 years of age completed 24 weeks of treatment (3 discontinued due to non-compliance). At Week 24, 54% achieved HIV RNA <50 copies/mL; 66% achieved HIV RNA <400 copies/mL. The mean CD4 count (percent) increase from baseline to Week 24 was 119 cells/mm3 (3.8%).

4 Weeks to Less Than 2 Years of Age

IMPAACT P1066 also enrolled HIV-infected, infants and toddlers 4 weeks to less than 2 years of age (Cohorts IV and V) who had received prior antiretroviral therapy either as prophylaxis for prevention of mother-to-child transmission (PMTCT) and/or as combination antiretroviral therapy for treatment of HIV infection. Raltegravir was administered as an oral suspension without regard to food in combination with an optimized background regimen.

The 26 subjects had a median age of 28 weeks (range: 4 -100), were 35% female, 85% Black and 8% Caucasian. At baseline, mean plasma HIV-1 RNA was 5.7 log10 copies/mL (range: 3.1 – 7), median CD4 cell count was 1400 cells/mm3 (range: 131 – 3648) and median CD4% was 18.6% (range: 3.3 – 39.3). Overall, 69% had baseline plasma HIV-1 RNA exceeding 100,000 copies/mL and 23% had a CDC HIV clinical classification of category B or C. None of the 26 subjects were completely treatment naïve. All infants under 6 months of age had received nevirapine or zidovudine for prevention of mother-to-infant transmission, and 43% of subjects greater than 6 months of age had received two or more antiretrovirals.

Of the 26 treated subjects, 23 subjects were included in the Week 24 and 48 efficacy analyses, respectively. All 26 treated subjects were included for safety analyses.

At Week 24, 39% achieved HIV RNA <50 copies/mL and 61% achieved HIV RNA <400 copies/mL. The mean CD4 count (percent) increase from baseline to Week 24 was 500 cells/mm3 (7.5%).

At Week 48, 44% achieved HIV RNA <50 copies/mL and 61% achieved HIV RNA <400 copies/mL. The mean CD4 count (percent) increase from baseline to Week 48 was 492 cells/mm3 (7.8%).

How Supplied/Storage and Handling

Isentress tablets 400 mg are pink, oval-shaped, film-coated tablets with "227" on one side. They are supplied as follows:

  NDC 0006-0227-61 unit-of-use bottles of 60.   No. 3894

Isentress HD tablets 600 mg are yellow, oval-shaped, film-coated tablets with Merck logo and "242" on one side and plain on the other side. They are supplied as follows:

  NDC 0006-3080-01 unit-of-use bottles of 60.   No. 3080

Isentress tablets 100 mg are pale orange, oval-shaped, orange-banana flavored, chewable tablets scored on both sides and imprinted on one face with the Merck logo and "477" on opposite sides of the score. They are supplied as follows:

  NDC 0006-0477-61 unit-of-use bottles of 60.   No. 3972

Isentress tablets 25 mg are pale yellow, round, orange-banana flavored, chewable tablets with the Merck logo on one side and "473" on the other side. They are supplied as follows:

  NDC 0006-0473-61 unit-of-use bottles of 60.   No. 3965

Isentress for oral suspension 100 mg is a white to off-white granular powder that may contain yellow or beige to tan particles, in child resistant single-use foil packets, packaged as a kit with two 5 mL dosing syringes and two mixing cups. It is supplied as follows:

  NDC 0006-3603-60 unit of use carton with 60 packets.   NDC 0006-3603-01 individual packet.   No. 3603

Storage and Handling

400 mg Film-coated Tablets, 600 mg Film-coated Tablets, Chewable Tablets and For Oral Suspension

Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F). See USP Controlled Room Temperature.

400 mg Film-coated Tablets, 600 mg Film-coated Tablets and Chewable Tablets

Store in the original package with the bottle tightly closed. Keep the desiccant in the bottle to protect from moisture.

For Oral Suspension

Store in the original container. Do not open foil packet until ready for use.

Warnings

Contraindications

None

Cautions

Risk of immune reconstitution syndrome if used with HAART

Autoimmune disorders (eg, Graves’ disease, polymyositis, Guillain-Barré syndrome) reported in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment

Concomitant medications known to increase risk of myopathy or rhabdomyolysis

Coadministration with drugs that are strong inducers of UGT1A1 may result in reduced plasma concentrations of raltegravir

Drug rash with eosinophilia and systemic symptoms (DRESS) reported

Severe, potentially life-threatening and fatal skin reactions reported; skin reactions include cases of Stevens-Johnson syndrome, hypersensitivity reaction and toxic epidermal necrolysis; immediately discontinue treatment if severe hypersensitivity, severe rash, or rash with systemic symptoms or liver aminotransferase elevations develops and monitor clinical status, including liver aminotransferases closely

Phenylketonurics: Chewable tablets contain phenylalanine, a component of aspartame

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