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Raltegravir Potassium

Pronunciation

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: Dutrebis, Isentress

Warning(s)

  • Fixed Combinations
  • If using lamivudine/raltegravir (Dutrebis), consider that lactic acidosis and severe hepatomegaly with steatosis, including fatalities, reported in patients receiving HIV nucleoside reverse transcriptase inhibitors (NRTIs) in conjunction with other antiretrovirals.241

  • If using lamivudine/raltegravir, consider that severe, acute exacerbations of HBV reported following discontinuance of lamivudine in HIV-infected patients coinfected with HBV.241 Monitor hepatic function with both clinical and laboratory follow-up for at least several months after discontinuance of lamivudine-containing preparations in coinfected patients.241 If appropriate, initiation of HBV treatment may be warranted.241

Introduction

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

Uses for Raltegravir Potassium

Treatment of HIV Infection

Treatment of HIV-1 infection in antiretroviral-naive (have not previously received antiretroviral therapy) or antiretroviral-experienced (previously treated) adults, adolescents, and pediatric patients ≥4 weeks of age;1 8 14 usually used in conjunction with 2 HIV NRTIs.1 200 201

For initial treatment in antiretroviral-naive adults and adolescents, experts state that raltegravir in conjunction with tenofovir disoproxil fumarate (tenofovir DF) and emtricitabine (or lamivudine) is a recommended INSTI-based regimen.200 Raltegravir in conjunction with abacavir and lamivudine (or emtricitabine) is an INSTI-based regimen option for initial treatment when recommended or alternative regimens cannot be used, but use only in those who are human leukocyte antigen (HLA)-B*5701 negative.200

For initial treatment in pediatric patients, experts state that an INSTI-based regimen of raltegravir and 2 NRTIs is an alternative regimen in those ≥2 years of age;201 also can be considered in infants and children 4 weeks to <2 years of age weighing ≥3 kg in special circumstances when preferred or alternative regimens cannot be used.201

Lamivudine/raltegravir fixed combination (Dutrebis) is used in conjunction with other antiretrovirals in adults, adolescents, and pediatric patients ≥6 years of age.241

Postexposure Prophylaxis following Occupational Exposure to HIV

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.199

USPHS recommends 3-drug regimen of raltegravir and emtricitabine and tenofovir DF as preferred regimen for PEP following occupational exposures to HIV.199 Alternative dual NRTIs for use with raltegravir are tenofovir DF and lamivudine, zidovudine and lamivudine, or zidovudine and emtricitabine.199

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.199 Do not delay initiation of PEP while waiting for expert consultation.199

Raltegravir Potassium 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 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
Oral

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

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

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.)

Cautions for Raltegravir Potassium

Contraindications

  • Raltegravir (Isentress): Manufacturer states none known.1

  • Lamivudine/raltegravir (Dutrebis): Hypersensitivity to lamivudine, raltegravir, or any component of the fixed combination;241 consider contraindications associated with both drugs in the fixed combination.241 (See Use of Fixed Combinations under Cautions.)

Warnings/Precautions

Sensitivity Reactions

Severe Skin and Hypersensitivity Reactions

Severe, potentially life-threatening skin reactions reported, including some fatalities.1 241 Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction (including hepatic failure) have occurred.1 241

Immediately discontinue raltegravir, lamivudine/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.1 241 Monitor clinical status, including liver aminotransferases, and initiate appropriate therapy.1 241

Life-threatening reactions could occur if discontinuance of raltegravir, lamivudine/raltegravir, and any other suspect agents is delayed after onset of severe rash.1 241

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),1 which is metabolized in the GI tract to phenylalanine.104 105

Each 25- or 100-mg raltegravir (Isentress) chewable tablet provides approximately 0.05 or 0.1 mg of phenylalanine, respectively.1

Interactions

Concomitant use of raltegravir or lamivudine/raltegravir with drugs that are potent inducers of UGT1A1 (e.g., rifampin) may result in decreased plasma concentrations of raltegravir.1 241 (See Interactions.)

Musculoskeletal Effects

Increased serum CK concentrations, myopathy, and rhabdomyolysis reported.1 241

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.1

Individuals with HBV or HCV Infection

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.1

If lamivudine/raltegravir used in HIV-infected patients coinfected with HBV or HCV, consider that additional precautions apply to these coinfected patients.241 (See Use of Fixed Combinations under Cautions.)

Use of Fixed Combinations

Lamivudine/raltegravir: Consider cautions, precautions, contraindications, and interactions associated with each drug in the fixed combination.241 Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for each drug.241

Because antiretrovirals contained in lamivudine/raltegravir may also be available in single-entity or other fixed-combination preparations, take care to ensure that therapy is not duplicated.241

Do not use lamivudine/raltegravir concomitantly with any preparation containing lamivudine, raltegravir, or emtricitabine.241

If lamivudine/raltegravir used, consider that lactic acidosis and severe hepatomegaly with steatosis, including fatalities, reported in patients receiving HIV NRTIs alone or in conjunction with other antiretrovirals.241 Discontinue lamivudine/raltegravir if clinical or laboratory findings indicate lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked increases in serum aminotransferase concentrations.241

If lamivudine/raltegravir used in patients coinfected with HIV and HBV, consider that severe, acute exacerbations of HBV infection reported following discontinuance of lamivudine in coinfected patients.241 Closely monitor hepatic function (using both clinical and laboratory follow-up) for at least several months after lamivudine/raltegravir discontinued.241 If appropriate, initiation of HBV treatment may be warranted.241 Safety and efficacy of lamivudine/raltegravir not established for treatment of chronic HBV infection.241

If lamivudine/raltegravir used in patients coinfected with HIV and HCV, consider that hepatic decompensation, sometimes fatal, reported in some patients receiving HIV NRTIs (e.g., lamivudine) concomitantly with peginterferon alfa (or interferon alfa) with or without ribavirin.109 241 Closely monitor such patients for toxicity, especially hepatic decompensation.109 241 Consider discontinuing lamivudine/raltegravir as medically appropriate.241 Consider dosage reduction or discontinuance of peginterferon alfa (or interferon alfa) and/or ribavirin if worsening clinical toxicities, including hepatic decompensation (e.g., Child-Pugh score >6), occur.109 241

Adipogenic Effects

Possible redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance.241

Mechanisms and long-term consequences of adipogenic effects unknown;241 causal relationship not established.241

Immune Reconstitution Syndrome

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

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) 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.1

Specific Populations

Pregnancy

Raltegravir (Isentress): Category C.1

Lamivudine/raltegravir (Dutrebis): Category C.241

Antiretroviral Pregnancy Registry at 800-258-4263 or .1 202 241

No adequate and well-controlled studies of raltegravir or lamivudine/raltegravir in pregnant women;1 241 manufacturer states use during pregnancy only if potential benefits to the woman outweigh risks to the fetus.1 241

Experts state that raltegravir and 2 NRTIs is a preferred INSTI-based regimen for initial treatment in pregnant women, especially when drug interactions with PI-based regimens are a concern.202

Lactation

Raltegravir distributed into milk in rats;1 202 241 not known whether distributed into human milk.1 202 241

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.1 202 241

Pediatric Use

Raltegravir (Isentress): Safety and efficacy not established in pediatric patients <4 weeks of age.1 Safety profile in infants, children, and adolescents 4 weeks to 18 years of age is similar to that in adults.1

Lamivudine/raltegravir (Dutrebis): Do not use in pediatric patients <6 years of age or in those weighing <30 kg.241 Use with caution in pediatric patients with a history of prior therapy with HIV NRTIs, a history of pancreatitis, or other clinically important risk factors for development of pancreatitis;241 discontinue immediately if there are signs, symptoms, or laboratory abnormalities suggestive of pancreatitis.241

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently to raltegravir (Isentress) or lamivudine/raltegravir (Dutrebis) than younger adults.1 241

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

Lamivudine/raltegravir: Monitor renal function.241 Consider that a switch from the fixed combination to single-entity lamivudine and single-entity raltegravir may be needed in patients with reduced renal function.241 (See Renal Impairment under Cautions.)

Hepatic Impairment

Raltegravir pharmacokinetics not altered in adults with moderate hepatic impairment;1 not studied in those with severe hepatic impairment.1

Risk for further elevations in hepatic enzyme concentrations in patients with chronic HBV or HCV infection.1

Lamivudine/raltegravir (Dutrebis): Safety and efficacy not established in patients with decompensated liver disease.241

Renal Impairment

Raltegravir pharmacokinetics not altered in adults with severe renal impairment.1 Not known if removed by dialysis;1 avoid administering drug before dialysis session.1 (See Renal Impairment under Dosage and Administration.)

Lamivudine/raltegravir (Dutrebis): Do not use if Clcr <50 mL/minute.241 Monitor renal function in those likely to have decreased renal function.241 Because lamivudine substantially eliminated by kidneys and decreased lamivudine dosage recommended in those with Clcr <50 mL/minute,200 241 switch to single-entity lamivudine and single-entity raltegravir to allow adjustment of lamivudine dosage in such patients.241

Common Adverse Effects

Insomnia, headache, dizziness, nausea, fatigue, hyperglycemia, decreased neutrophil count, and increased serum aminotransferases, total bilirubin, lipase, pancreatic amylase, CK, cholesterol.1

Interactions for Raltegravir Potassium

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: Decreased raltegravir concentrations200

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: Do not use concomitantly 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 buprenorphine pharmacokinetics200

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

Dosage adjustments not needed200

Dasabuvir

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

Ombitasvir/paritaprevir/ritonavir with dasabuvir: Dosage adjustments not needed180

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

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 necessary200

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

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

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

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 copackaged with dasabuvir: No clinically important interactions with raltegravir180 200

Ombitasvir/paritaprevir/ritonavir: Dosage adjustments not needed179

Ombitasvir/paritaprevir/ritonavir with dasabuvir: Dosage adjustments not needed180

Paritaprevir

Ombitasvir/paritaprevir/ritonavir copackaged with dasabuvir: No clinically important interactions with raltegravir180 200

Ombitasvir/paritaprevir/ritonavir: Dosage adjustments are not needed179

Ombitasvir/paritaprevir/ritonavir with dasabuvir: Dosage adjustments not needed180

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

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

Raltegravir Potassium Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability of raltegravir not established.1

Raltegravir (Isentress) chewable tablets and oral suspension are not bioequivalent to raltegravir film-coated tablets;1 oral bioavailability is higher with chewable tablets or oral suspension compared with film-coated tablets.1

Raltegravir film-coated tablets in fasting adults: Peak plasma concentrations attained in approximately 3 hours.1 With twice-daily dosing, steady state achieved within approximately 2 days.1

Raltegravir chewable tablets in pediatric patients weighing >25 kg: Lower trough plasma concentrations compared with film-coated tablets.1

Bioavailability of raltegravir contained in lamivudine/raltegravir (Dutrebis) is higher than that of raltegravir contained in single-entity raltegravir.241

A film-coated tablet of lamivudine/raltegravir (lamivudine 150 mg and raltegravir 300 mg) provides lamivudine and raltegravir exposures comparable to a 150-mg lamivudine tablet and a 400-mg raltegravir tablet taken simultaneously.241

Food

Studies using raltegravir film-coated tablets indicate food may increase pharmacokinetic variability, but effect not considered clinically important.1

Raltegravir chewable tablets: AUC decreased 6% when administered with high-fat meal compared with administration in fasting state.1

Raltegravir film-coated tablets: Administration with low-fat meal decreased AUC by 46%, administration with moderate-fat meal (600 Kcal, 21 g fat) increased AUC by approximately 13%, and administration with high-fat meal increased AUC by approximately twofold compared with administration in fasting state.1

Raltegravir oral suspension: Effect of food not studied.1

Lamivudine/raltegravir film-coated tablets: Administration with high-fat meal decreased raltegravir and lamivudine trough concentrations by 23 and 21%, respectively, compared with administration in fasting state;241 raltegravir and lamivudine AUCs were similar to those observed in fasted state.241

Distribution

Extent

Raltegravir distributed into CSF; clinical importance unknown.1

Crosses human placenta.202

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

Plasma Protein Binding

83%.1

Elimination

Metabolism

Raltegravir metabolized mainly by UGT1A1-mediated glucuronidation in the liver.1 200

Elimination Route

Raltegravir excreted in feces (51%) and urine (32%).1

Not known if removed by dialysis.1

Half-life

9 hours.1

Special Populations

Moderate hepatic impairment: No clinically important differences in raltegravir pharmacokinetics compared with healthy individuals.1

Severe hepatic impairment: Raltegravir pharmacokinetics not studied.1

Severe renal impairment: No clinically important differences in raltegravir pharmacokinetics compared with healthy individuals.1

Infants, children, and adolescents 4 weeks to 18 years of age receiving recommended pediatric dosage: Raltegravir pharmacokinetics similar to that reported in adults receiving 400 mg twice daily.1

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.1

Stability

Storage

Oral

Chewable Tablets

Raltegravir (Isentress): 20–25°C (may be exposed to 15–30°C).1

Keep bottle tightly closed; do not remove desiccant.1

Film-coated Tablets

Raltegravir (Isentress): 20–25°C (may be exposed to 15–30°C).1

Lamivudine/raltegravir (Dutrebis): 20–25°C (may be exposed to 15–30°C).241 Store in original package and keep bottle tightly closed;241 do not remove desiccant.241

Oral Suspension

Raltegravir (Isentress): 20–25°C.1 Do not open single-use foil packet of powder for oral suspension until ready to use.1

After suspending packet contents in water, discard suspension if not used within 30 minutes.1

Actions and Spectrum

  • Raltegravir inhibits catalytic 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); 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

Advice to Patients

  • Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.1 241 Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1 241

  • Importance of using single-entity raltegravir (Isentress) or fixed combination lamivudine/raltegravir (Dutrebis) in conjunction with other antiretrovirals—not for monotherapy.1 241

  • Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.1 241

  • Advise patients that sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to acquired immunodeficiency disease (AIDS) and death.1 241

  • 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.1 200 241 Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never sharing personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reusing or sharing needles.1 200 241

  • Importance of reading patient information provided by the manufacturer.1 241

  • If using raltegravir film-coated tablets, importance of swallowing whole;1 raltegravir chewable tablets can be chewed or swallowed whole.1

  • 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.1 Instruct parents and/or caregivers that the oral suspension should be administered within 30 minutes of mixing.1

  • Advise patients not to take aluminum- and/or magnesium-containing antacids during raltegravir or lamivudine/raltegravir treatment.1 241

  • If a dose of raltegravir or lamivudine/raltegravir is missed, the dose should be taken as soon as it is remembered and the next dose taken at the regularly scheduled time.1 241 If a dose is skipped, a double dose should not be taken to make up for the missed dose.1 241

  • Importance of informing clinician if unusual symptoms develop or known symptoms persist or worsen.1

  • Redistribution/accumulation of body fat may occur with antiretroviral therapy, with as yet unknown long-term health effects.241

  • Advise patients that severe and potentially life-threatening rash has been reported.1 241 Importance of immediately discontinuing raltegravir or lamivudine/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).1 241

  • 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).1 241 Importance of immediately informing clinician if unexplained muscle pain, tenderness, or weakness occurs.1 241

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal products, and any concomitant illnesses.1 241

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 241 Advise HIV-infected women not to breast-feed.1

  • Importance of advising patients of other important precautionary information.1 241 (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

Raltegravir Potassium Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

300 mg (of raltegravir) with Lamivudine 150 mg

Dutrebis

Merck

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

References

1. Merck Sharp & Dohme. Isentress (raltegravir) film-coated tablets, chewable tablets, and for oral suspension prescribing information. Whitehouse Station, NJ; 2015 Feb

2. Steigbigel RT, Cooper DA, Teppler H et al. Long-term efficacy and safety of Raltegravir combined with optimized background therapy in treatment-experienced patients with drug-resistant HIV infection: week 96 results of the BENCHMRK 1 and 2 Phase III trials. Clin Infect Dis. 2010; 50:605-12. [PubMed 20085491]

4. Grinsztejn B, Nguyen BY, Katlama C et al for Protocol 005 team. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. Lancet. 2007; 369:1261-9. [PubMed 17434401]

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

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

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

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

15. Nachman S, Zheng N, Acosta EP et al. Pharmacokinetics, safety, and 48-week efficacy of oral raltegravir in HIV-1-infected children aged 2 through 18 years. Clin Infect Dis. 2013; :. [PubMed 24145879]

17. Rockstroh JK, DeJesus E, Lennox JL et al. Durable efficacy and safety of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected patients: final 5-year results from STARTMRK. J Acquir Immune Defic Syndr. 2013; 63:77-85. [PubMed 23412015]

18. Eron JJ, Cooper DA, Steigbigel RT et al. Efficacy and safety of raltegravir for treatment of HIV for 5 years in the BENCHMRK studies: final results of two randomised, placebo-controlled trials. Lancet Infect Dis. 2013; 13:587-96. [PubMed 23664333]

19. Marinello J, Marchand C, Mott BT et al. Comparison of raltegravir and elvitegravir on HIV-1 integrase catalytic reactions and on a series of drug-resistant integrase mutants. Biochemistry. 2008; 47:9345-54. [PubMed 18702518]

20. Blanco JL, Varghese V, Rhee SY et al. HIV-1 integrase inhibitor resistance and its clinical implications. J Infect Dis. 2011; 203:1204-14. [PubMed 21459813]

21. Garrido C, Villacian J, Zahonero N et al. Broad phenotypic cross-resistance to elvitegravir in HIV-infected patients failing on raltegravir-containing regimens. Antimicrob Agents Chemother. 2012; 56:2873-8. [PubMed 22450969]

22. Goethals O, Clayton R, Van Ginderen M et al. Resistance mutations in human immunodeficiency virus type 1 integrase selected with elvitegravir confer reduced susceptibility to a wide range of integrase inhibitors. J Virol. 2008; 82:10366-74. [PubMed 18715920]

23. Underwood MR, Johns BA, Sato A et al. The activity of the integrase inhibitor dolutegravir against HIV-1 variants isolated from raltegravir-treated adults. J Acquir Immune Defic Syndr. 2012; 61:297-301. [PubMed 22878423]

104. Food and Drug Administration. Food additives permitted for direct addition to food for human consumption; aspartame. Final rule. [21 CFR Part 172] Fed Regist. 1983; 48:31376 82.

105. Anon. Aspartame and other sweeteners. Med Lett Drugs Ther. 1982; 24:1 2.

109. Genentech USA, Inc. Pegasys (peginterferon alfa-2a) injection for subcutaneous use prescribing information. South San Francisco, CA; 2015 Mar.

179. AbbVie, Inc. Technivie (ombitasvir, paritaprevir, and ritonavir) tablets prescribing information. North Chicago, IL; 2015 Jul.

180. AbbVie, Inc. Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) tablets prescribing information. North Chicago, IL; 2015 Mar.

181. Gilead Sciences, Inc. Harvoni (ledipasvir and sofosbuvir) tablets prescribing information. Foster City, CA; 2015 Mar.

187. Janssen Products LP. Olysio (simeprevir) capsules prescribing information. Titusville, NJ; 2015 Apr.

188. Gilead Sciences Inc. Sovaldi (sofosbuvir) tablets prescribing information. Foster City, CA; 2015 Mar.

199. Kuhar DT, Henderson DK, Struble KA et al. Updated US Public Health Service guidelines for the management of occupational exposures to human immunodeficiency virus and recommendations for postexposure prophylaxis. Infect Control Hosp Epidemiol. 2013; 34:875-92. [PubMed 23917901]

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (April 8, 2015). Updates may be available at HHS AIDS Information (AIDSinfo) website.

201. Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in pediatric HIV infection (April 27, 2015). Updates may be available at HHS AIDS Information (AIDSinfo) website.

202. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, US Department of Health and Human Services (HHS). Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States (August 6, 2015). Updates may be available at HHS AIDS Information (AIDSinfo) website.

205. ViiV Healthcare. Lexiva (fosamprenavir calcium) tablets and oral suspension prescribing information. Research Triangle Park, NC; 2012 Feb.

214. Janssen. Intelence (etravirine) tablets prescribing information. Raritan, NJ; 2012 Aug.

224. ViiV Healthcare. Selzentry (maraviroc) tablets prescribing information. Research Triangle Park, NC; 2015 Apr.

226. Janssen Therapeutics. Edurant (rilpivirine) tablets prescribing information. Titusville, NJ; 2015 Aug.

235. Gilead Sciences. Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) tablets prescribing information. Foster City, CA; 2013 Oct.

236. ViiV Healthcare. Tivicay (dolutegravir) tablets prescribing information. Research Triangle Park, NC; Aug 2015.

237. Janssen Therapeutics. Prezcobix (darunavir/cobicistat) tablets prescribing information. Titusville, NJ; 2015 Jan.

241. Merck Sharp & Dohme. Dutrebis(lamivudine and raltegravir) tablets prescribing information. Whitehouse Station, NJ; 2015 Feb.

242. Gilead Sciences Inc. Vitekta (elvitegravir) tablets prescribing information. Foster City, CA; 2015 Jul.

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