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

Introduction

Antiretroviral; HIV integrase inhibitor.^{1 200}

Uses for Raltegravir Potassium

Treatment of HIV Infection

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

For initial treatment in antiretroviral-naive adults and adolescents, raltegravir in conjunction with tenofovir and emtricitabine (or lamivudine) is a preferred regimen and raltegravir in conjunction with abacavir and lamivudine (or emtricitabine) is an alternative regimen.²⁰⁰

Slideshow: Grapefruit and Medicines: A Possible Deadly Mix?

Regimens containing raltegravir not recommended for initial treatment in antiretroviral-naive pediatric patients because of limited data.²⁰¹

Safety and efficacy not established in pediatric patients <2 years of age.¹

Raltegravir Potassium Dosage and Administration

Administration

Oral Administration

Administer orally without regard to food.¹

Chewable Tablets

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

Used in children 2 to <12 years of age weighing ≥10 kg.¹

Film-coated Tablets

Must be swallowed whole.¹

Used in adults, adolescents, or children ≥6 years of age weighing ≥25 kg.¹

Dosage

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

Must be given in conjunction with other antiretrovirals.¹

Chewable tablets and film-coated tablets are not bioequivalent;¹ chewable tablets should not be substituted for the 400-mg film-coated tablet.¹

Pediatric Patients

Treatment of HIV Infection

Oral

Children 2 to <6 years of age weighing ≥10 kg (chewable tablets): Dosage based on weight (approximately 6 mg/kg twice daily; up to maximum of 300 mg twice daily).¹ (See Table 1.)

Children 6 to <12 years of age weighing ≥25 kg (film-coated tablets): 400 mg twice daily (one 400-mg film-coated tablet twice daily).¹

Children 6 to <12 years of age (chewable tablets): Dosage based on weight (approximately 6 mg/kg twice daily; up to maximum of 300 mg twice daily).¹ (See Table 1.)

Children and adolescents ≥12 years of age (film-coated tablets): 400 mg twice daily (one 400-mg film-coated tablet twice daily).¹

Table 1. Dosage of Raltegravir (Chewable Tablets) in Children 2 to <12 Years of Age Weighing ≥10 kg

Body Weight (kg)	Dosage	Number of Chewable Tablets
10 to <14	75 mg twice daily	three 25-mg tablets twice daily
14 to <20	100 mg twice daily	one 100-mg tablet twice daily
20 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

Adults

Treatment of HIV Infection

Oral

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

Prescribing Limits

Pediatric Patients

Treatment of HIV Infection

Children 2 to <12 Years of Age

Oral

Chewable tablets: Maximum 300 mg twice daily.¹

Special Populations

Hepatic Impairment

Dosage adjustment not necessary in patients with mild to moderate hepatic impairment;^{1 200} data are not available in patients with severe hepatic impairment.¹ (See Hepatic Impairment under Cautions.)

Renal Impairment

Dosage adjustment not necessary.^{1 200} Avoid administering drug before dialysis session.¹ (See Renal Impairment under Cautions.)

Geriatric Patients

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

Cautions for Raltegravir Potassium

Contraindications

• Manufacturer states none known.¹

Warnings/Precautions

Sensitivity Reactions

Severe Skin and Hypersensitivity Reactions

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

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.¹ Monitor clinical status, including liver aminotransferases, and initiate appropriate therapy.¹

Life-threatening reactions could occur if there is a delay in discontinuing raltegravir or other suspect agents after onset of severe rash.¹

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 jiroveci [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

Phenylketonuria

Advise individuals with phenylketonuria (i.e., homozygous genetic deficiency of phenylalanine hydroxylase) and other individuals who must restrict phenylalanine intake that raltegravir chewable tablets contain aspartame (NutraSweet),¹ which is metabolized in the GI tract to phenylalanine.^{104 105}

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

Interactions

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

Musculoskeletal Effects

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

Use with caution in patients at increased risk of myopathy or rhabdomyolysis, including those receiving concomitant therapy with drugs associated with myopathy or rhabdomyolysis.¹

Specific Populations

Pregnancy

Category C.¹

Antiretroviral Pregnancy Registry at 800-258-4263 or .^{1 202}

Experts state that safety and pharmacokinetic data are limited, but use can be considered in pregnant women in special circumstances when preferred and alternative antiretrovirals cannot be used.²⁰²

Lactation

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

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

Pediatric Use

Safety profile in children and adolescents 2–18 years of age is similar to that in adults.¹

Safety and efficacy not established in pediatric patients <2 years of age.¹

Geriatric Use

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

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

Hepatic Impairment

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

Renal Impairment

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

Common Adverse Effects

Insomnia, headache, nausea, fatigue.¹

Interactions for Raltegravir Potassium

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

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

Does not inhibit P-glycoprotein-mediated transport.¹

Drugs Affecting or Metabolized by Uridine Diphosphate-glucuronosyltransferase 1A1

Potential pharmacokinetic interactions with drugs that are potent inducers of UGT 1A1 (decreased plasma concentrations of raltegravir)^{1 200} or inhibitors of UGT 1A1 (increased plasma concentrations of raltegravir).¹

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

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

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

Drugs Metabolized by P-Glycoprotein Transport System

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

Specific Drugs

Drug	Interaction	Comments
Abacavir	In vitro evidence of additive to synergistic antiretroviral effects1
Amprenavir	In vitro evidence of additive to synergistic antiretroviral effects1
Anticonvulsants (phenobarbital, phenytoin)	Phenytoin and/or phenobarbital potentially may affect the UGT 1A1 pathway;11 effect on raltegravir pharmacokinetics unknown1	Concomitant use of phenytoin and/or phenobarbital was prohibited in expanded-access program due to potential effect on UGT 1A1 pathway11
Antimycobacterials, rifamycins (rifabutin, rifampin, rifapentine)	Rifabutin: Increased raltegravir concentrations and AUC200 Rifampin: Decreased peak plasma concentrations and AUC of raltegravir1 11 200	Rifabutin: Dosage adjustments not needed200 Rifampin: In adults, increase dosage of raltegravir film-coated tablets to 800 mg twice daily and monitor closely for virologic response;1 200 data insufficient to make dosage recommendations for concomitant use in children and adolescents <18 years of age1 Rifapentine: Concomitant use not recommended200
Atazanavir	Atazanavir or ritonavir-boosted atazanavir: Increased raltegravir concentrations and AUC1 200 In vitro evidence of additive to synergistic antiretroviral effects1	Atazanavir (with or without low-dose ritonavir): Dosage adjustments not needed1 200
Benzodiazepines (e.g., midazolam)	Raltegravir not expected to affect pharmacokinetics of midazolam1 10
Boceprevir	Pharmacokinetic interactions not expected200	Dosage adjustments not needed200
Buprenorphine	No clinically important effect on buprenorphine pharmacokinetics200	Dosage adjustments not needed200
Darunavir	Ritonavir-boosted darunavir: Decreased raltegravir AUC;200 no clinically important effect on pharmacokinetics of ritonavir-boosted darunavir1	Ritonavir-boosted darunavir: Dosage adjustments not needed200
Delavirdine	In vitro evidence of additive to synergistic antiretroviral effects1
Didanosine	In vitro evidence of additive to synergistic antiretroviral effects1
Efavirenz	Decreased raltegravir concentrations and AUC;1 11 200 clinical importance unknown11 In vitro evidence of additive to synergistic antiretroviral effects1	Some experts state dosage adjustments not needed200
Enfuvirtide	In vitro evidence of additive to synergistic antiretroviral effects1
Etravirine	Decreased raltegravir concentrations and AUC; no clinically important effect on etravirine pharmacokinetics;1 200 214 clinical importance unknown1 No in vitro evidence of antagonistic antiretroviral effects214	Dosage adjustments not needed200 214
Estrogens/progestins	No clinically important effect on pharmacokinetics of hormonal contraceptives1 200	May be used concomitantly200
Fosamprenavir	Fosamprenavir or ritonavir-boosted fosamprenavir: Decreased concentrations and AUCs of raltegravir and amprenavir (active metabolite of fosamprenavir)205	Fosamprenavir (with or without low-dose ritonavir): Appropriate dosages for concomitant use with respect to safety and efficacy not established;205 some experts state dosage adjustments not necessary200
Indinavir	In vitro evidence of additive to synergistic antiretroviral effects1
Lamivudine	No clinically important effect on lamivudine pharmacokinetics1 In vitro evidence of additive to synergistic antiretroviral effects1
Lopinavir/ritonavir	Decreased raltegravir concentrations; no change in lopinavir/ritonavir concentrations200 In vitro evidence of additive to synergistic antiretroviral effects1	Dosage adjustments not needed200
Maraviroc	Decreased raltegravir concentrations and AUC;200 224 decreased maraviroc concentrations and AUC200 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	No clinically important effect on methadone pharmacokinetics1 200	Dosage adjustments not needed200
Nelfinavir	In vitro evidence of additive to synergistic antiretroviral effects1
Nevirapine	In vitro evidence of additive to synergistic antiretroviral effects1
Omeprazole	Substantially increased raltegravir concentrations and AUC1 200	Dosage adjustments not needed1 200
Rilpivirine	Data not available;200 clinically important interaction unlikely226 No in vitro evidence of antagonistic antiretroviral effects 226
Ritonavir	Low-dose ritonavir: Decreased raltegravir peak concentrations and AUC1 200 In vitro evidence of additive to synergistic antiretroviral effects1	Dosage adjustments not needed;200 consider possibility of drug interactions between raltegravir and other protease inhibitors (PIs) when low-dose ritonavir is used to boost PI concentrations11
Saquinavir	In vitro evidence of additive to synergistic antiretroviral effects1
Stavudine	In vitro evidence of additive to synergistic antiretroviral effects1
Tenofovir	Increased raltegravir concentrations and AUC; no clinically important effect on tenofovir pharmacokinetics1 200 In vitro evidence of additive to synergistic antiretroviral effects1	Dosage adjustments not needed200
Telaprevir	Increased raltegravir concentrations and AUC; no clinically important effect on telaprevir concentrations or AUC184 200	Dosage adjustments not needed200
Tipranavir	Ritonavir-boosted tipranavir: Decreased raltegravir concentrations and AUC1 200	Ritonavir-boosted tipranavir: Dosage adjustments not needed1 200
Zidovudine	In vitro evidence of additive to synergistic antiretroviral effects1

Raltegravir Potassium Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability not established.¹

Chewable tablets and film-coated tablets are not bioequivalent;¹ oral bioavailability is higher with chewable tablet compared with film-coated tablet.¹

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

Food

Chewable tablet: AUC decreased 6% when administered with high-fat meal compared with administration in fasting state.¹

Film-coated tablet: AUC increased by approximately 13% when administered with moderate-fat meal compared with administration in fasting state.¹

Distribution

Extent

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

Crosses human placenta.²⁰²

Plasma Protein Binding

83%.¹

Elimination

Metabolism

Metabolized mainly by UGT 1A1-mediated glucuronidation in the liver.^{1 200}

Elimination Route

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

Not known if removed by dialysis.¹

Half-life

9 hours.¹

Special Populations

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

Severe hepatic impairment: Pharmacokinetics not studied.¹

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

Children and adolescents 2–18 years of age receiving recommended pediatric dosage: Pharmacokinetic profile similar to that reported in adults receiving 400 mg twice daily.¹

Stability

Storage

Oral

Chewable Tablets

20–25°C (may be exposed to 15–30°C).¹

Keep bottle tightly closed; do not remove desiccant.¹

Film-coated Tablets

20–25°C (may be exposed to 15–30°C).¹

Actions

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

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

• Also has some activity against HIV type 2 (HIV-2).¹

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

Advice to Patients

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

• Importance of using in conjunction with other antiretrovirals—not for monotherapy.¹

• Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.¹ Sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to AIDS and death.¹

• 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.²⁰⁰ 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}

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

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

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

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

• Advise patients that severe and potentially life-threatening rash has been reported.¹ 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).¹

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

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

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

Preparations

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

Raltegravir Potassium

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablet, chewable	25 mg (of raltegravir)	Isentress	Merck
		100 mg (of raltegravir)	Isentress	Merck
	Tablet, film-coated	400 mg (of raltegravir)	Isentress	Merck

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2013. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Isentress 400MG Tablets (MERCK SHARP &amp; DOHME): 60/$1,030.04 or 180/$3,030.04