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Raltegravir

Class: HIV 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
Brands: Isentress

Medically reviewed by Drugs.com on Sep 28, 2020. Written by ASHP.

Introduction

Antiretroviral; HIV integrase strand transfer inhibitor (INSTI).

Uses for Raltegravir

Treatment of HIV Infection

Treatment of HIV-1 infection in antiretroviral-naive (have not previously received antiretroviral therapy) or antiretroviral-experienced (previously treated) adults and pediatric patients weighing 2 kg or more; usually used in conjunction with 2 HIV nucleoside reverse transcriptase inhibitors (dual NRTIs).

For initial treatment in antiretroviral-naive adults and adolescents, experts state that a 3-drug regimen of raltegravir in conjunction with a tenofovir prodrug (tenofovir alafenamide fumarate [TAF] or tenofovir disoproxil fumarate [TDF; tenofovir DF]) and emtricitabine or lamivudine is a recommended INSTI-based regimen for most patients.

Experts state that a 2-drug regimen of ritonavir-boosted darunavir (once daily) and raltegravir (twice daily) can be considered for initial treatment in antiretroviral-naive adults when abacavir, TAF, and TDF cannot be used or are not optimal and patient has a plasma HIV-1 RNA level <100,000 copies/mL and CD4+ T-cell count >200 cells/mm3. However, do not use this 2-drug regimen in patients with HIV-1 resistant to darunavir or raltegravir and do not use in those coinfected with HBV.

Most appropriate antiretroviral regimen cannot be defined for every clinical scenario; select regimen based on information regarding antiretroviral potency, potential rate of resistance development, known toxicities, potential for pharmacokinetic interactions, and patient's virologic, immunologic, and clinical characteristics. Guidelines for the management of HIV infection, including specific recommendations for initial treatment in antiretroviral-naive patients and recommendations for changing antiretroviral regimens, are available at [Web].

Postexposure Prophylaxis following Occupational Exposure to HIV (PEP)

Postexposure prophylaxis of HIV infection following occupational exposure (PEP) in health-care personnel and others exposed via percutaneous injury (e.g., needlestick, cut with sharp object) or mucous membrane or nonintact skin (e.g., chapped, abraded, dermatitis) contact with blood, tissue, or other body fluids that might contain HIV.

USPHS recommends 3-drug regimen of raltegravir and emtricitabine and TDF as preferred regimen for PEP following occupational exposures to HIV. Alternative dual NRTIs for use with raltegravir are TDF and lamivudine, zidovudine and lamivudine, or zidovudine and emtricitabine.

Management of occupational exposures to HIV is complex and evolving; consult infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or National Clinicians’ Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) whenever possible. Do not delay initiation of PEP while waiting for expert consultation.

Postexposure Prophylaxis following Nonoccupational Exposure to HIV (nPEP)

Postexposure prophylaxis of HIV infection following nonoccupational exposure (nPEP) in individuals exposed to blood, genital secretions, or other potentially infectious body fluids that might contain HIV when the exposure represents a substantial risk for HIV transmission. Used in conjunction with other antiretrovirals.

When nPEP indicated in adults and adolescents ≥13 years of age with normal renal function, CDC states preferred regimen is either raltegravir or dolutegravir used in conjunction with emtricitabine and TDF (given as the fixed combination emtricitabine/TDF); recommended alternative in these patients is ritonavir-boosted darunavir used in conjunction with emtricitabine/TDF.

Consult infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians’ Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) if nPEP indicated in certain exposed individuals (e.g., pregnant women, children, those with medical conditions such as renal impairment) or if considering a regimen not included in CDC guidelines, source virus is known or likely to be resistant to antiretrovirals, or healthcare provider is inexperienced in prescribing antiretrovirals. Do not delay initiation of nPEP while waiting for expert consultation.

Raltegravir Dosage and Administration

Administration

Oral Administration

Administer orally once or twice daily without regard to food. Use in conjunction with other antiretrovirals.

Raltegravir (Isentress) 25- or 100-mg chewable tablets and 400-mg film-coated tablets: Administer twice daily.

Raltegravir (Isentress HD) 600-mg film-coated tablets: Administer once daily.

Raltegravir (Isentress) powder for oral suspension: Administer once or twice daily depending on age.

Chewable Tablets

May be chewed or swallowed whole. If needed, 100-mg chewable tablets can be divided into equal halves.

Used in pediatric patients ≥4 weeks of age weighing ≥11 to <25 kg. If needed, may be used as alternative in pediatric patients weighing ≥25 kg who cannot swallow film-coated tablets; however, the film-coated tablets are preferred in pediatric patients weighing ≥25 kg.

Film-coated Tablets

Must be swallowed whole.

400-mg film-coated tablets: Used in adults and pediatric patients weighing ≥25 kg.

600-mg film-coated tablets: Used in adults and pediatric patients weighing ≥40 kg.

Oral Suspension

Used in pediatric patients weighing 2 to <20 kg.

Immediately prior to use, contents of a single-use packet of powder for oral suspension must be mixed in 10 mL of water to provide a suspension containing 10 mg/mL. Appropriate dosage of the suspension is then administered orally using dosing syringe provided by the manufacturer.

To prepare oral suspension, use dosing syringe provided by the manufacturer to measure and add 10 mL of water to the mixing cup provided by the manufacturer. Open a single-dose packet of powder for oral suspension and add entire contents to the water in the mixing cup, tightly close mixing cup, and gently swirl for 45 seconds. If powder not completely mixed, gently swirl mixing cup some more. Do not shake; suspension will appear cloudy.

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

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

Dosage

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

Raltegravir chewable tablets and oral suspension are not bioequivalent to raltegravir film-coated tablets; do not substitute chewable tablets or oral suspension for the 400- or 600-mg film-coated tablets.

Pediatric Patients

Treatment of HIV-1 Infection
Full-term Neonates Weighing ≥2 kg
Oral

Use powder for oral suspension in full-term neonates (birth through 4 weeks [28 days] of age) weighing ≥2 kg. Dosage is based on weight; use once-daily regimen in neonates up to 1 week of age and use twice-daily regimen in those 1–4 weeks of age. (See Table 1.)

If the mother received a dose of raltegravir (Isentress or Isentress HD) within 2–24 hours before delivery, give first raltegravir dose in the neonate 24–48 hours after birth.

Recommended dosage of raltegravir oral suspension in neonates from birth to 1 week of age is based on approximately 1.5 mg/kg per dose.

Recommended dosage of raltegravir oral suspension in neonates 1–4 weeks of age is based on approximately 3 mg/kg per dose.

Table 1. Recommended Dosage of Raltegravir Oral Suspension (Isentress) in Full-term Neonates (Birth to 4 Weeks of Age) Weighing ≥2 kg1

Weight (kg)

Volume (Dose) of Oral Suspension Containing 10 mg/mL

Birth to 1 Week of Age (Once-daily Regimen)

2 to <3

0.4 mL (4 mg) once daily

3 to <4

0.5 mL (5 mg) once daily

4 to <5

0.7 mL (7 mg) once daily

1–4 Weeks of Age (Twice-daily Regimen)

2 to <3

0.8 mL (8 mg) twice daily

3 to <4

1 mL (10 mg) twice daily

4 to <5

1.5 mL (15 mg) twice daily

Pediatric Patients ≥4 weeks of Age Weighing 3 to <25 kg
Oral

Use powder for oral suspension in those weighing 3 to <11 kg; use either powder for oral suspension or chewable tablets in those weighing 11 to <20 kg; and use chewable tablets in those weighing 20 to <25 kg. Dosage is based on weight and depends on whether powder for oral suspension or chewable tablets are used. Use twice-daily regimen in these pediatric patients. (See Table 2.)

Recommended weight-based dosage of oral suspension or chewable tablets in pediatric patients ≥4 weeks of age weighing 3 to <25 kg is based on approximately 6 mg/kg twice daily.

In those weighing 11 to <20 kg, may use either the recommended dosage of oral suspension or recommended dosage of chewable tablets.

The 100-mg chewable tablets can be divided into equal halves.

Table 2. Recommended Dosage of Raltegravir Oral Suspension or Chewable Tablets (Isentress) in Pediatric Patients ≥4 Weeks of Age Weighing 3 to <25 kg1

Weight (kg)

Volume (Dose) of Oral Suspension Containing 10 mg/mL

Number of 25- or 100-mg Chewable Tablets

3 to <4

2.5 mL (25 mg) twice daily

Do not use

4 to <6

3 mL (30 mg) twice daily

Do not use

6 to <8

4 mL (40 mg) twice daily

Do not use

8 to <11

6 mL (60 mg) twice daily

Do not use

11 to <14

8 mL (80 mg) twice daily

Three 25-mg tablets twice daily

14 to <20

10 mL (100 mg) twice daily

One 100-mg tablet twice daily

20 to <25

Do not use

One and one-half 100-mg tablets twice daily

Pediatric Patients Weighing ≥25 kg Who are Unable to Swallow Film-coated Tablets
Oral

Film-coated tablets are preferred, but may use chewable tablets in those unable to swallow the film-coated tablets. When chewable tablets used, dosage is based on weight and twice-daily regimen is used. (See Table 3.)

Recommended weight-based dosage of chewable tablets in pediatric patients weighing ≥25 kg is based on approximately 6 mg/kg twice daily.

The 100-mg chewable tablets can be divided into equal halves.

Table 3. Recommended Dosage of Raltegravir Chewable Tablets (Isentress) In Pediatric Patients Weighing ≥25 kg and Unable to Swallow the Film-coated Tablets1

Weight (kg)

Dosage

Number of 100-mg 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

Pediatric Patients Weighing 25 to <40 kg Who are Able to Swallow Film-coated Tablets
Oral

400 mg twice daily (one 400-mg film-coated tablet twice daily).

Pediatric Patients Weighing ≥40 kg
Oral

400 mg twice daily (one 400-mg film-coated tablet twice daily). Alternatively, 1.2 g once daily (two 600-mg film-coated tablets once daily).

Virologically suppressed on initial regimen of raltegravir 400 mg twice daily: Continue same twice-daily regimen or switch to 1.2 g once daily (two 600-mg film-coated tablets once daily).

Adults

Treatment of HIV-1 Infection
Antiretroviral-naive Adults
Oral

400 mg twice daily (one 400-mg film-coated tablet twice daily). Alternatively, 1.2 g once daily (two 600-mg film-coated tablets once daily).

Adults receiving rifampin: 800 mg twice daily (two 400-mg film-coated tablets twice daily).

Antiretroviral-experienced Adults
Oral

400 mg twice daily (one 400-mg film-coated tablet twice daily).

Virologically suppressed on initial regimen of raltegravir 400 mg twice daily: Continue same twice-daily regimen or switch to 1.2 g once daily (two 600-mg film-coated tablets once daily).

Adults receiving rifampin: 800 mg twice daily (two 400-mg film-coated tablets twice daily).

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

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

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

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

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

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.

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

Prescribing Limits

Pediatric Patients

Treatment of HIV Infection
Pediatric Patients Weighing ≥2 to <20 kg
Oral

Oral suspension: Maximum 100 mg twice daily.

Pediatric Patients ≥4 Weeks of Age Weighing ≥11 to <25 kg
Oral

Chewable tablets: Maximum 300 mg twice daily.

Special Populations

Hepatic Impairment

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

Raltegravir (once daily): Not recommended. (See Hepatic Impairment under Cautions.)

Renal Impairment

Raltegravir (once or twice daily): Dosage adjustments not needed in patients with renal impairment. Avoid administering raltegravir before dialysis session. (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. (See Geriatric Use under Cautions.)

Cautions for Raltegravir

Contraindications

  • Manufacturer states none known.

Warnings/Precautions

Sensitivity Reactions

Severe Skin and Hypersensitivity Reactions

Severe, potentially life-threatening skin reactions, including some fatalities, reported. Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction (including hepatic failure) have occurred.

Immediately discontinue raltegravir and any other suspect agents if signs or symptoms of severe skin or hypersensitivity reactions occur, including (but not limited to) severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, or angioedema. Monitor clinical status, including liver aminotransferases, and initiate appropriate therapy.

Life-threatening reactions could occur if discontinuance of raltegravir and any other suspect agents is delayed after onset of severe rash.

Interactions

Concomitant use of raltegravir with drugs that are potent inducers of UGT1A1 (e.g., rifampin) may result in decreased plasma concentrations of raltegravir. (See Interactions.)

Musculoskeletal Effects

Increased serum CK concentrations, myopathy, and rhabdomyolysis reported.

Use with caution in patients at increased risk of myopathy or rhabdomyolysis, including those receiving concomitant therapy with drugs known to cause myopathy or rhabdomyolysis (e.g., hydroxymethylglutaryl-CoA [HMG-CoA] reductase inhibitors [statins], fenofibrate, gemfibrozil, zidovudine) and those with history of rhabdomyolysis, myopathy, or increased serum CK concentrations.

HIV-infected Individuals Coinfected with HBV or HCV

Safety profile of raltegravir in HIV-infected patients with HBV or HCV coinfection is similar to that in HIV-infected patients without such coinfection, but increased AST and ALT concentrations reported more frequently.

Immune Reconstitution Syndrome

During initial treatment, HIV-infected patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium, M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jirovecii); this may necessitate further evaluation and treatment.

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) also reported to occur in the setting of immune reconstitution; time to onset is more variable and can occur many months after initiation of antiretroviral therapy.

Pharmacogenomics

Phenylketonuria

Advise individuals with phenylketonuria (i.e., homozygous genetic deficiency of phenylalanine hydroxylase) and other individuals who must restrict phenylalanine intake that raltegravir (Isentress) chewable tablets contain aspartame (NutraSweet), which is metabolized in the GI tract to phenylalanine.

Each 25- or 100-mg raltegravir chewable tablet (Isentress) provides approximately 0.05 or 0.1 mg of phenylalanine, respectively.

UGT1A1 Polymorphism

Raltegravir metabolized primarily by UGT1A. However, common UGT1A1 polymorphisms do not appear to alter pharmacokinetics of the drug to any clinically important extent.

In a study in adults, raltegravir AUC in those with UGT1A1*28/*28 genotype (associated with reduced UGT1A1 activity) was compared to AUC in those with wild-type UGT1A1 genotype; geometric mean AUC ratio was 1.41.

In a neonatal clinical trial (IMPAACT P1110), there was no association between apparent clearance of raltegravir and UGT1A1 polymorphisms. Raltegravir dosage recommendations for neonates <4 weeks of age take into consideration the rapidly increasing UGT1A1 activity and drug clearance that occurs from birth to 4 weeks of age; UGT1A1 catalytic activity is negligible at birth and matures after birth.

Specific Populations

Pregnancy

Antiretroviral Pregnancy Registry at 800-258-4263 or [Web].

Raltegravir readily crosses human placenta.

Available data from the Antiretroviral Pregnancy Registry show no difference in the rate of overall birth defects in infants of pregnant women receiving raltegravir compared with the background rate of major birth defects in the US. In animal studies (rats and rabbits), no evidence of adverse developmental outcomes when raltegravir given orally during organogenesis at doses producing exposures approximately 4 times those reported with maximum recommended human dose.

Experts state that raltegravir (twice daily) is a preferred antiretroviral for use in 3-drug antiretroviral regimens for treatment of HIV-1 infection in antiretroviral-naive and previously treated pregnant women and in women of childbearing potential trying to conceive. Although raltegravir plasma concentrations and AUC may be decreased during pregnancy, this is not considered clinically important and adjustment of raltegravir dosage during pregnancy not warranted. However, experts state do not use once-daily raltegravir regimens in pregnant women pending further accumulation of data.

Lactation

Not known whether distributed into human milk; distributed into milk in rats.

Not known whether raltegravir affects human milk production or affects the breast-fed infant.

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.

Pediatric Use

Raltegravir (Isentress): Labeled by FDA for use in pediatric patients weighing ≥2 kg; not recommended in preterm neonates or pediatric patients weighing <2 kg.

Raltegravir (Isentress HD): Labeled by FDA for use in pediatric patients weighing ≥40 kg. Although not studied in pediatric patients, manufacturer states that population pharmacokinetic modeling and simulation support use of the once-daily regimen (two 600-mg film-coated tablets once daily) in those weighing ≥40 kg.

Safety and pharmacokinetics of the oral suspension were evaluated in full-term HIV-1 exposed neonates at high risk of acquiring HIV-1 infection in a clinical trial (IMPAACT P1110). Safety profile of the drug in these neonates was comparable to that observed in adults receiving the drug.

Safety, efficacy, and pharmacokinetics of twice-daily raltegravir were evaluated in HIV-1 infected pediatric patients 4 weeks to 18 years of age in a clinical trial, (IMPAACT P1066). Safety profile of the drug in these pediatric patients was comparable to that observed in adults receiving the drug.

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults. Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Hepatic Impairment

Pharmacokinetics of a single 400-mg dose not altered in adults with moderate hepatic impairment; not studied in those with severe hepatic impairment.

Once-daily raltegravir regimen (two 600-mg film-coated tablets once daily) not recommended in patients with hepatic impairment; pharmacokinetics of raltegravir (once daily) not studied in such patients.

Risk for further elevations in hepatic enzyme concentrations in patients with chronic HBV or HCV infection.

Renal Impairment

Pharmacokinetics of a single 400-mg dose not altered in adults with severe renal impairment (Clcr <30 mL/minute per 1.73 m2).

Pharmacokinetics of once-daily regimen (two 600-mg film-coated tablets once daily) not evaluated in patients with renal impairment.

Because renal clearance is a minor elimination pathway for unchanged raltegravir, dosage adjustment of raltegravir (once or twice daily) not needed in patients with any degree of renal impairment.

Extent of removal by dialysis not known; avoid administering before dialysis session. (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Insomnia, headache, dizziness, nausea, fatigue, hyperglycemia, decreased neutrophil count, and increased serum aminotransferases, total bilirubin, lipase, pancreatic amylase, CK, cholesterol.

Interactions for Raltegravir

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

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

Does not inhibit P-glycoprotein (P-gp) transport.

Drugs Affecting or Metabolized by UGT

UGT1A1 inducers: Possible decreased raltegravir plasma concentrations.

UGT1A1 inhibitors: Possible increased raltegravir plasma concentrations.

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.

Specific Drugs

Drug

Interaction

Comments

Abacavir

No in vitro evidence of antagonistic antiretroviral effects

α1-Adrenergic blocking agents (alfuzosin, doxazosin, silodosin, tamsulosin, terazosin)

Raltegravir not expected to affect α1-adrenergic blocking agent concentrations

Dosage adjustments not needed

β-Adrenergic blocking agents

Metoprolol, timolol: Raltegravir not expected to affect β-adrenergic blocking agent concentrations

Metoprolol, timolol: Dosage adjustments not needed

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

Aluminum- and/or magnesium-containing antacids: Decreased raltegravir concentrations and AUC

Calcium-containing antacids: Decreased raltegravir concentrations and AUC in those receiving raltegravir (twice daily)

Aluminum- and/or magnesium-containing antacids: Do not use in patients receiving raltegravir; use alternative acid-reducing agent

Calcium-containing antacids: Dosage adjustments not needed if used concomitantly with raltegravir (twice daily); concomitant use with raltegravir (once daily) not recommended

Antiarrhythmic agents

Amiodarone, digoxin, disopyramide, dofetilide, dronedarone, flecainide, systemic lidocaine, mexiletine, propafenone, quinidine: Raltegravir not expected to affect concentrations of these antiarrhythmic agents

Amiodarone, digoxin, disopyramide, dofetilide, dronedarone, flecainide, systemic lidocaine, mexiletine, propafenone, quinidine: Dosage adjustments not needed

Anticoagulants

Apixaban, betrixaban, dabigatran, edoxaban, rivaroxaban: Raltegravir not expected to affect concentrations of these anticoagulants

Warfarin: Raltegravir not expected to affect warfarin concentrations

Apixaban, betrixaban, dabigatran, edoxaban, rivaroxaban: Dosage adjustments not needed

Warfarin: Dosage adjustments not needed

Anticonvulsants

Carbamazepine: Effect on raltegravir pharmacokinetics unknown

Eslicarbazepine: Possible decreased raltegravir concentrations

Ethosuximide, lamotrigine: Raltegravir not expected to affect concentrations of these anticonvulsants

Oxcarbazepine, phenobarbital, phenytoin: Possible decreased raltegravir concentrations

Valproic acid: Data not available

Carbamazepine: Concomitant use not recommended

Eslicarbazepine: Some experts state consider alternative anticonvulsant or alternative antiretroviral

Ethosuximide, lamotrigine: Dosage adjustments not needed

Oxcarbazepine, phenobarbital, phenytoin: Concomitant use not recommended; consider alternative anticonvulsant or alternative antiretroviral

Valproic acid: Some experts recommend monitoring valproic acid concentrations and virologic response if used with raltegravir

Antidiabetic agents

Metformin: Raltegravir not expected to affect metformin concentrations

Saxagliptin or fixed combination of dapagliflozin and saxagliptin (dapagliflozin/saxagliptin): Raltegravir not expected to affect concentrations of these antidiabetic agents

Metformin: Dosage adjustments not needed

Saxagliptin, dapagliflozin/saxagliptin: Dosage adjustments not needed

Antifungals, azoles

Itraconazole, posaconazole, voriconazole: Pharmacokinetic interactions not expected if used with raltegravir

Itraconazole, posaconazole, voriconazole: Dosage adjustments not needed

Antimycobacterials, rifamycins (rifabutin, rifampin, rifapentine)

Rifabutin: Increased raltegravir AUC

Rifampin: Decreased raltegravir concentrations and AUC

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

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

Rifampin: In adults receiving raltegravir (twice daily), increase dosage of raltegravir to 800 mg twice daily and monitor closely for virologic response or consider use of rifabutin instead; concomitant use with raltegravir (once daily) not recommended; data insufficient to make dosage recommendations for concomitant use in pediatric patients

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

Antiplatelet agents

Clopidogrel, prasugrel, ticagrelor, vorapaxar: Raltegravir not expected to affect concentrations of these antiplatelet agents

Clopidogrel, prasugrel, ticagrelor, vorapaxar: Dosage adjustments not needed

Antipsychotic agents

Aripiprazole, brexpiprazole, cariprazine, iloperidone, lurasidone, pimavanserin, pimozide, quetiapine, ziprasidone: Raltegravir not expected to affect concentrations of these antipsychotic agents

Aripiprazole, brexpiprazole, cariprazine, iloperidone, lurasidone, pimavanserin, pimozide, quetiapine, ziprasidone: Dosage adjustments not needed

Atazanavir

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

Cobicistat-boosted atazanavir: Data not available

No in vitro evidence of antagonistic antiretroviral effects

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Dosage adjustments not needed

Benzodiazepines

Clonazepam, clorazepate, diazepam, estazolam, flurazepam, triazolam: Raltegravir not expected to affect concentrations of these benzodiazepines

Midazolam: No clinically important effects on midazolam pharmacokinetics

Clonazepam, clorazepate, diazepam, estazolam, flurazepam, midazolam, triazolam: Dosage adjustments not needed

Bosentan

Raltegravir not expected to affect bosentan concentrations

Dosage adjustments not needed

Buprenorphine

Buprenorphine (buccal, sublingual, subdermal implant): Raltegravir not expected to affect buprenorphine or norbuprenorphine concentrations

Dosage adjustments not needed

Bupropion

Raltegravir not expected to affect bupropion concentrations

Dosage adjustments not needed

Buspirone

Raltegravir not expected to affect buspirone concentrations

Dosage adjustments not needed

Calcifediol

Raltegravir not expected to affect calcifediol concentrations

Dosage adjustments not needed

Calcium-channel blocking agents

No pharmacokinetic interactions with raltegravir expected

Dosage adjustments not needed

Calcium supplements

Possible decreased raltegravir concentrations

Some experts recommend giving raltegravir ≥2 hours before or ≥6 hours after oral supplements containing calcium

Colchicine

Raltegravir not expected to affect colchicine concentrations

Dosage adjustments not needed

Corticosteroids

Betamethasone, budesonide, dexamethasone, prednisone, prednisolone (systemic): Raltegravir not expected to affect concentrations of these systemic corticosteroids

Beclomethasone, budesonide, ciclesonide, fluticasone, mometasone (orally inhaled or intranasal): Raltegravir not expected to affect concentrations of these corticosteroids

Betamethasone, methylprednisolone, prednisolone, triamcinolone (intra-articular, epidural, intraorbital): Raltegravir not expected to affect concentrations of these corticosteroids

Betamethasone, budesonide, dexamethasone, prednisone, prednisolone (systemic): Dosage adjustments not needed

Beclomethasone, budesonide, ciclesonide, fluticasone, mometasone (orally inhaled or intranasal): Dosage adjustments not needed

Betamethasone, methylprednisolone, prednisolone, triamcinolone (intra-articular, epidural, intraorbital): Dosage adjustments not needed

Darunavir

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

Cobicistat-boosted darunavir: Data not available

Ritonavir-boosted or cobicistat-boosted darunavir: Dosage adjustments not needed if used with raltegravir

Delavirdine

No in vitro evidence of antagonistic antiretroviral effects

Didanosine

No in vitro evidence of antagonistic antiretroviral effects

Dolutegravir

No in vitro evidence of antagonistic antiretroviral effects

Doravirine

No pharmacokinetic interactions expected

No in vitro evidence of antagonistic antiretroviral effects

Dosage adjustments not needed

Dronabinol

Raltegravir not expected to affect dronabinol concentrations

Dosage adjustments not needed

Efavirenz

Decreased raltegravir concentrations and AUC; not considered clinically important

No in vitro evidence of antagonistic antiretroviral effects

Dosage adjustments not needed if used with raltegravir (twice daily); concomitant use with raltegravir (once daily) not recommended

Elbasvir and grazoprevir

Elbasvir: No clinically important pharmacokinetic interactions with raltegravir

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

Fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir): Dosage adjustments not needed

Eluxadoline

Raltegravir not expected to affect eluxadoline concentrations

Dosage adjustments not needed

Enfuvirtide

No in vitro evidence of antagonistic antiretroviral effects

Eplerenone

Raltegravir not expected to affect eplerenone concentrations

Dosage adjustments not needed

Ergot alkaloids (dihydroergotamine, ergotamine, methylergonovine)

Raltegravir not expected to affect concentrations of ergot alkaloids

Dosage adjustments not needed

Estrogens and progestins

Estradiol, estrogen, conjugated estrogens: Raltegravir not expected to affect concentrations of these estrogens

Drospirenone, medroxyprogesterone, progesterone: Raltegravir not expected to affect concentrations of these hormones

Oral contraceptives containing ethinyl estradiol and norgestimate: Raltegravir has no effect on pharmacokinetics of ethinyl estradiol or norgestimate

Estradiol, estrogen, conjugated estrogens: Dosage adjustments not needed

Drospirenone, medroxyprogesterone, progesterone: Dosage adjustments not needed

Oral contraceptives containing ethinyl estradiol and norgestimate: Dosage adjustments not needed

Etravirine

Decreased raltegravir concentrations and AUC (not clinically important); no clinically important effect on etravirine pharmacokinetics

No in vitro evidence of antagonistic antiretroviral effects

Dosage adjustments not needed if used concomitantly with raltegravir

Fentanyl

Raltegravir not expected to affect fentanyl concentrations

Dosage adjustments not needed

Flibanserin

Raltegravir not expected to affect flibanserin concentrations

Dosage adjustments not needed

Fosamprenavir

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

No in vitro evidence of antagonistic antiretroviral effects with amprenavir

Fosamprenavir or ritonavir-boosted fosamprenavir: Appropriate dosages for concomitant use with respect to safety and efficacy not established

Glecaprevir and Pibrentasvir

Fixed combination of glecaprevir and pibrentasvir (glecaprevir/pibrentasvir): No clinically important pharmacokinetic interactions

Glecaprevir/pibrentasvir: Dosage adjustments not needed

Goserelin

Raltegravir not expected to affect goserelin concentrations

Dosage adjustments not needed

Histamine H2-receptor antagonists

Increased raltegravir concentrations and AUC

Dosage adjustments not needed

HMG-CoA reductase inhibitors (statins)

Atorvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin: Raltegravir not expected to affect concentrations of these statins

Dosage adjustments not needed

Immunosuppressive agents

Cyclosporine, everolimus, sirolimus, tacrolimus: Raltegravir not expected to affect concentrations of these immunosuppressive agents

Cyclosporine, everolimus, sirolimus, tacrolimus: Dosage adjustments not needed

Indinavir

No vitro evidence of antagonistic antiretroviral effects

Iron preparations

Possible decreased raltegravir concentrations

Some experts recommend giving raltegravir ≥2 hours before or ≥6 hours after oral supplements containing iron

Ivabradine

Raltegravir not expected to affect ivabradine concentrations

Dosage adjustments not needed

Lamivudine

No clinically important effects on lamivudine pharmacokinetics

No in vitro evidence of antagonistic antiretroviral effects

Dosage adjustments not needed if lamivudine used with raltegravir

Ledipasvir and sofosbuvir

Ledipasvir: No clinically important effects on pharmacokinetics of raltegravir or ledipasvir

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

Ledipasvir/sofosbuvir: Dosage adjustments not needed

Leuprolide

Raltegravir not expected to affect leuprolide concentrations

Dosage adjustments not needed

Lofexidine

Raltegravir not expected to affect lofexidine concentrations

Dosage adjustments not needed

Lomitapide

Raltegravir not expected to affect lomitapide concentrations

Dosage adjustments not needed

Lopinavir/ritonavir

Decreased raltegravir concentrations; no change in lopinavir/ritonavir concentrations

No in vitro evidence of antagonistic antiretroviral effects

Dosage adjustments not needed

Macrolides

Azithromycin, clarithromycin, erythromycin: Raltegravir not expected to affect macrolide concentrations

Azithromycin, clarithromycin, erythromycin: Dosage adjustments not needed

Maraviroc

Decreased raltegravir AUC and decreased maraviroc AUC

Some experts state dosage adjustments not needed

Methadone

No clinically important effects on methadone pharmacokinetics

Dosage adjustments not needed

Nefazodone

Raltegravir not expected to affect nefazodone concentrations

Dosage adjustments not needed

Nelfinavir

No in vitro evidence of antagonistic antiretroviral effects

Nevirapine

Data not available

No in vitro evidence of antagonistic antiretroviral effects

Some experts state dosage adjustments not needed

Phosphodiesterase (PDE) type 5 inhibitors

Avanafil, sildenafil, tadalafil, vardenafil: Raltegravir not expected to affect concentrations of these PDE5 inhibitors

Avanafil, sildenafil, tadalafil, vardenafil: Dosage adjustments not needed

Proton-pump inhibitors

Omeprazole: Increased raltegravir concentrations and AUC; not considered clinically important

Not expected to have clinically important effects on pharmacokinetics of proton-pump inhibitors

Omeprazole or other proton-pump inhibitors: Dosage adjustments not needed

Ranolazine

Raltegravir not expected to affect ranolazine concentrations

Dosage adjustments not needed

Rilpivirine

Increased raltegravir concentrations; not considered clinically important

No in vitro evidence of antagonistic antiretroviral effects

Dosage adjustments not needed

Selective β-adrenergic agonists

Arformoterol, formoterol, indacaterol, olodaterol, salmeterol (orally inhaled): Raltegravir not expected to affect concentrations of the β-adrenergic agonist

Arformoterol, formoterol, indacaterol, olodaterol, salmeterol (orally inhaled): Dosage adjustments not needed

Saquinavir

No in vitro evidence of antagonistic antiretroviral effects

Sofosbuvir

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

Dosage adjustments not needed

Sofosbuvir and velpatasvir

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

Sofosbuvir/velpatasvir: Dosage adjustments not needed

Sofosbuvir, velpatasvir, and voxilaprevir

Fixed combination of sofosbuvir, velpatasvir, and voxilaprevir (sofosbuvir/velpatasvir/voxilaprevir): No clinically important pharmacokinetic interactions expected

Sofosbuvir/velpatasvir/voxilaprevir: Dosage adjustments not needed

Spironolactone

Raltegravir not expected to affect spironolactone concentrations

Dosage adjustments not needed

SSRIs

Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline: No pharmacokinetic interactions with raltegravir expected

Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline: Dosage adjustments not needed

Stavudine

No in vitro evidence of antagonistic antiretroviral effects

Sucralfate

Possible decreased raltegravir concentrations

Some experts recommend giving raltegravir ≥2 hours before or ≥6 hours after sucralfate

Suvorexant

Raltegravir not expected to affect suvorexant concentrations

Dosage adjustments not needed

Tenofovir

Tenofovir alafenamide fumarate (TAF): Pharmacokinetic interactions not expected

Tenofovir disoproxil fumarate (TDF): Increased raltegravir concentrations and AUC (not clinically important); no clinically important effects on tenofovir pharmacokinetics

No in vitro evidence of antagonistic antiretroviral effects

TDF: Dosage adjustments not needed

Testosterone

Raltegravir not expected to affect testosterone concentrations

Dosage adjustments not needed

Tipranavir

Ritonavir-boosted tipranavir: Decreased raltegravir concentrations and AUC; not considered clinically important

Ritonavir-boosted tipranavir: Dosage adjustments not needed if used with raltegravir (twice daily); concomitant use with raltegravir (once daily) not recommended

Tramadol

Raltegravir not expected to affect tramadol concentrations

Dosage adjustments not needed

Trazodone

Raltegravir not expected to affect trazodone concentrations

Dosage adjustments not needed

Tricyclic antidepressants

Amitriptyline, desipramine, doxepin, imipramine, nortriptyline: Raltegravir not expected to affect concentrations of these tricyclic antidepressants

Amitriptyline, desipramine, doxepin, imipramine, nortriptyline: Dosage adjustments not needed

Zidovudine

No in vitro evidence of antagonistic antiretroviral effects

Zolpidem

Raltegravir not expected to affect zolpidem concentrations

Dosage adjustments not needed

Raltegravir Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability of raltegravir not established.

Oral bioavailability is higher with raltegravir chewable tablets and oral suspension than with raltegravir 400-mg film-coated tablets; the 600-mg film-coated tablets have higher relative bioavailability compared to the 400-mg film-coated tablets.

Because the formulations have different pharmacokinetic profiles, the chewable tablets and oral suspension are not bioequivalent to the film-coated tablets.

Raltegravir (Isentress) 400-mg film-coated tablets in fasting adults: Peak plasma concentrations attained in approximately 3 hours.

Raltegravir (Isentress HD) 600-mg film-coated tablets: Peak plasma concentrations attained in approximately 1.5–2 hours after a dose.

Increases in peak plasma concentrations and AUC are dose proportional or slightly less than dose proportional over the dose range of 100 mg to 1.6 g.

Film-coated tablets: Steady state attained in 2 days with the twice-daily regimen (400 mg twice daily) or once-daily regimen (1.2 g once daily).

Chewable tablets in pediatric patients weighing >25 kg: Lower trough plasma concentrations compared with film-coated tablets.

Food

Studies using raltegravir chewable tablets, film-coated tablets, and powder for oral suspension indicate food affects peak plasma concentrations and AUC. Not considered clinically important.

Distribution

Extent

Raltegravir distributed into CSF; clinical importance unknown.

Readily crosses human placenta.

Not known whether distributed into human milk; distributed into milk in rats.

Plasma Protein Binding

Approximately 83%.

Elimination

Metabolism

Raltegravir metabolized primarily by UGT1A1-mediated glucuronidation in the liver. (See UGT1A1 Polymorphism in Cautions.)

Elimination Route

Raltegravir excreted in feces (51%) and urine (32%).

Extent of removal by dialysis not known.

Half-life

Approximately 9 hours.

Special Populations

Moderate hepatic impairment: Study using single 400-mg dose indicates no clinically important differences in raltegravir pharmacokinetics compared with healthy individuals. Pharmacokinetics after 1.2 g once daily (two 600-mg film-coated tablets once daily) in patients with hepatic impairment not studied.

Severe hepatic impairment: Raltegravir pharmacokinetics not studied.

Severe renal impairment (Clcr <30 mL/minute per 1.73 m2): Study using single 400-mg dose indicates no clinically important differences in raltegravir pharmacokinetics compared with healthy individuals. Pharmacokinetics after 1.2 g once daily (two 600-mg film-coated tablets once daily) in patients with renal impairment not studied.

Infants, children, and adolescents 4 weeks to 18 years of age receiving recommended pediatric dosage: Raltegravir pharmacokinetics similar to those reported in adults receiving 400 mg twice daily.

Common UGT1A1 genotypes associated with reduced UGT1A1 activity do not appear to have clinically important effect on raltegravir pharmacokinetics compared with wild-type UGT1A1 genotype.

Stability

Storage

Oral

Chewable Tablets

Raltegravir (Isentress): 20–25°C (may be exposed to 15–30°C).

Keep bottle tightly closed; do not remove desiccant.

Film-coated Tablets

Raltegravir (Isentress, Isentress HD): 20–25°C (may be exposed to 15–30°C).

Keep bottle tightly closed; do not remove desiccant.

Oral Suspension

Raltegravir (Isentress): 20–25°C (may be exposed to 15–30°C).

Do not open single-use foil packet of powder for oral suspension until ready to use.

After suspending packet contents in water, discard suspension if not used within 30 minutes.

Actions and Spectrum

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

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

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

  • Cross-resistance between raltegravir and other INSTIs (e.g., dolutegravir, elvitegravir) reported.

Advice to Patients

  • Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician. Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.

  • Importance of using raltegravir in conjunction with other antiretrovirals—not for monotherapy.

  • Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.

  • Advise patients that sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to acquired immunodeficiency disease (AIDS) and death.

  • Advise patients that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others. Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids) and reducing high-risk behaviors (e.g., reusing or sharing needles).

  • Importance of reading patient information provided by the manufacturer.

  • If using raltegravir film-coated tablets, importance of swallowing whole; raltegravir chewable tablets can be chewed or swallowed whole. Inform patients with phenylketonuria that the chewable tablets contain aspartame.

  • If using raltegravir for oral suspension, importance of parents and/or caregivers reading the manufacturer's instructions for use before preparing and administering the oral suspension. Instruct parents and/or caregivers that the oral suspension should be administered within 30 minutes of mixing.

  • If a dose of raltegravir is missed, the dose should be taken as soon as it is remembered and the next dose taken at the regularly scheduled time. If a dose is skipped, a double dose should not be taken to make up for the missed dose.

  • Advise patients that severe and potentially life-threatening rash has been reported. Importance of immediately discontinuing raltegravir and other suspect agents and seeking medical attention if rash occurs and is associated with fever, generally ill feeling, extreme tiredness, muscle or joint aches, breathing difficulty, blisters, oral lesions, eye inflammation, swelling of the face, eyes, lips, or mouth, and/or signs and symptoms of liver problems (e.g., yellowing of skin or whites of the eyes, dark or tea-colored urine, pale stools/bowel movements, nausea, vomiting, loss of appetite, or pain, aching, or sensitivity on the right side below ribs).

  • Importance of informing clinician if patient has a history of rhabdomyolysis, myopathy, or increased CK concentrations or is receiving drugs known to cause these conditions (e.g., statins, fenofibrate, gemfibrozil, zidovudine). Importance of immediately informing clinician if unexplained muscle pain, tenderness, or weakness occurs.

  • Advise patients that signs and symptoms of inflammation from previous infections may occur soon after initiation of antiretroviral therapy in some individuals. Importance of immediately informing clinicians if any signs or symptoms of infection occur.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal products, and any concomitant illnesses.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Advise HIV-infected women not to breast-feed.

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

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

600 mg (of raltegravir)

Isentress HD

Merck

AHFS DI Essentials™. © Copyright 2021, Selected Revisions September 28, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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