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Raltegravir

Pronunciation

(ral TEG ra vir)

Index Terms

  • MK-0518
  • RAL
  • Raltegravir Potassium

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Packet, Oral:

Isentress: 100 mg (1 ea, 60 ea) [contains polyethylene glycol; banana flavor]

Tablet, Oral:

Isentress: 400 mg

Isentress HD: 600 mg

Tablet Chewable, Oral:

Isentress: 25 mg [contains aspartame, saccharin sodium; orange banana flavor]

Isentress: 100 mg [scored; contains aspartame, saccharin sodium; orange banana flavor]

Brand Names: U.S.

  • Isentress
  • Isentress HD

Pharmacologic Category

  • Antiretroviral, Integrase Inhibitor (Anti-HIV)

Pharmacology

Incorporation of viral DNA into the host cell’s genome is required to produce a self-replicating provirus and propagation of infectious virion particles. The viral cDNA strand produced by reverse transcriptase is subsequently processed and inserted into the human genome by the enzyme HIV-1 integrase (encoded by the pol gene of HIV). Raltegravir inhibits the catalytic activity of integrase, thus preventing integration of the proviral gene into human DNA.

Absorption

Film-coated tablet (400 mg formulation): AUC increased twofold with high-fat meal; Chewable tablet: AUC decreased by ~6% with high-fat meal (not clinically significant); Oral suspension: The effect of food was not studied

Metabolism

Primarily hepatic glucuronidation mediated by UGT1A1

Excretion

Feces (~51%, as unchanged drug); urine (~32%; 9% as unchanged drug)

Time to Peak

Film-coated tablet (400 mg formulation): ~3 hours; film-coated tablet (600 mg formulation): ~1.5 to 2 hours

Half-Life Elimination

~9 hours

Protein Binding

~83%

Special Populations: Children

At birth, the enzyme responsible for the metabolism of raltegravir is low and increases over first 4 to 6 weeks of life (HHS [pediatric 2017]). In neonates <4 weeks of age, raltegravir competes with bilirubin for albumin protein binding sites and may increase unconjugated bilirubin concentrations; however, in vitro data suggests that this effect unlikely to be significant at typical serum concentration (HHS [perinatal 2017])

Use: Labeled Indications

HIV-1 infection, treatment: Treatment of HIV-1 infection in combination with other antiretroviral agents

Off Label Uses

HIV-1 nonoccupational postexposure prophylaxis

Based on the Centers for Disease Control and Prevention, US Department of Health and Human Services updated guidelines for antiretroviral postexposure prophylaxis after sexual, injection drug use, or other nonoccupational exposure to HIV, raltegravir (in conjunction with other antiretrovirals) is effective and recommended for postexposure prophylaxis of HIV-1 infection following nonoccupational exposure (nPEP) in individuals exposed to blood, genital secretions, or other potentially infectious body fluids that may contain HIV when that exposure represents a substantial risk for HIV transmission.

HIV-1 occupational postexposure prophylaxis

Based on the US Public Health Service updated guidelines for the management of occupational exposures to HIV and recommendations for postexposure prophylaxis, raltegravir (in combination with emtricitabine/tenofovir) is an effective and recommended treatment option for postexposure prophylaxis of HIV-1 infection in health care personnel following occupational exposure (oPEP) to blood and/or other body fluids that may contain HIV.

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Canadian labeling: Hypersensitivity to raltegravir or any other component of the formulation

Dosing: Adult

HIV-1 infection, treatment: Oral: Note: Raltegravir is a component of a recommended initial regimen with tenofovir plus emtricitabine (or lamivudine) or tenofovir alafenamide plus emtricitabine in ART-naive patients (HHS [adult] 2016); may also be used in combination with darunavir and ritonavir as part of a nucleoside-sparing regimen in ART-naïve patients with HIV-1 viral load <100,000 copies/mL and CD4 count >200 cells/mm3 (HHS [adult] 2016; Raffi 2014; Taiwo 2011).

Treatment-naïve patients: Film-coated tablet: 400 mg twice daily or 1,200 mg once daily (2 x 600 mg tablet). Note: Patients virologically suppressed on an initial regimen of raltegravir 400 mg twice daily may switch to 1,200 mg (2 x 600 mg tablet) once daily.

Treatment-experienced patients: Film-coated tablet: 400 mg twice daily.

HIV-1 nonoccupational postexposure prophylaxis (nPEP) (off-label use): Oral: Film-coated tablet: 400 mg twice daily for 28 days in combination with other antiretroviral agents. Initiate therapy within 72 hours of exposure (HHS [nPEP] 2016).

HIV-1 occupational postexposure, prophylaxis (oPEP) (off-label use): Oral: Film-coated tablet: 400 mg twice daily for 4 weeks with concomitant emtricitabine/tenofovir. Initiate therapy as soon as possible after occupational exposure (and within 72 hours) (Kuhar 2013).

Dosage adjustment for rifampin coadministration: Treatment-naïve or treatment-experienced patients: 800 mg twice daily.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

HIV-1 infection, treatment: Oral:

Note: Raltegravir film-coated tablets and chewable tablets or oral suspension are not bioequivalent and are not substitutable on a mg/mg basis

Oral suspension (20 mg/mL): Infants and Children weighing 3 to <20 kg:

Weight-directed dosing: 6 mg/kg/dose twice daily; maximum dose: 100 mg/dose

Fixed-dosing:

3 to <4 kg: 20 mg (1 mL) twice daily.

4 to <6 kg: 30 mg (1.5 mL) twice daily.

6 to <8 kg: 40 mg (2 mL) twice daily.

8 to <11 kg: 60 mg (3 mL) twice daily.

11 to <14 kg: 80 mg (4 mL) twice daily.

14 to <20 kg: 100 mg (5 mL) twice daily.

Chewable tablets: Children weighing ≥11 kg:

Weight-directed dosing: 6 mg/kg/dose twice daily; maximum dose: 300 mg/dose

Fixed-dosing:

11 to <14 kg: 75 mg (3 x 25 mg tablet) twice daily.

14 to <20 kg: 100 mg (1 x 100 mg tablet) twice daily.

20 to <28 kg: 150 mg (1.5 x 100 mg tablet) twice daily.

28 to <40 kg: 200 mg (2 x 100 mg tablet) twice daily.

≥40 kg: 300 mg (3 x 100 mg tablet) twice daily.

Film-coated tablets:

Children and Adolescents weighing ≥25 kg who are able to swallow a tablet whole: 400 mg twice daily.

Children and Adolescents weighing ≥40 kg who are treatment-naïve: 400 mg twice daily or 1,200 mg (2 x 600 mg tablet) once daily. Note: Patients virologically suppressed on an initial regimen of raltegravir 400 mg twice daily may switch to 1,200 mg (2 x 600 mg tablet) once daily.

Dosage adjustment for rifampin coadministration: There are no data to guide dose adjustment in patients <18 years.

HIV-1 nonoccupational postexposure prophylaxis (nPEP) (off-label use) (HHS [nPEP] 2016): Oral: Note: Initiate therapy within 72 hours of exposure and continue for 28 days; use in combination with other antiretroviral agents.

Infants and Children <2 years: Oral suspension: 6 mg/kg/dose twice daily

Children ≥2 years:

Chewable tablets:

11 to <14 kg: 75 mg twice daily

14 to <20 kg: 100 mg twice daily

20 to <28 kg: 150 mg twice daily

28 to <40 kg: 200 mg twice daily

≥40 kg: 300 mg twice daily

Film-coated tablet: Children ≥ 6 years weighing >25 kg who are able to swallow a tablet whole: 400 mg twice daily

Adolescents: Oral: Film-coated tablet: Refer to adult dosing.

Dosing: Renal Impairment

Mild, moderate, and severe impairment: No dosage adjustment necessary.

End-stage renal disease (ESRD) on intermittent hemodialysis (IHD): Dose after dialysis on dialysis days.

Dosing: Hepatic Impairment

Film-coated tablet (400 mg formulation), chewable tablet, oral suspension:

Mild-to-moderate impairment: No dosage adjustment necessary.

Severe impairment: There are no dosage adjustments provided in manufacturer’s labeling (has not been studied).

Film-coated tablet (600 mg formulation): Use is not recommended (has not been studied).

Administration

May be administered without regard to meals.

Chewable tablets: May be chewed or swallowed whole; the 100 mg chewable tablet may be divided into equal halves.

Film-coated tablets: Must be swallowed whole.

Oral suspension: Using provided mixing cup, pour packet contents into 5 mL water, close lid and swirl for 30 to 60 seconds. Do not turn the mixing cup upside down. Once mixed, measure recommended suspension dose with an oral syringe (concentration of suspension is 20 mg/mL). Administer within 30 minutes of mixing with water. Discard any remaining suspension in the trash.

Dietary Considerations

Some products may contain phenylalanine.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Film-coated and chewable tablets: Store in the original package; keep desiccant in the bottle to protect from moisture.

Oral suspension: Store in the original container; do not open foil packet until ready for reconstitution and use.

Drug Interactions

Aluminum Hydroxide: May decrease the serum concentration of Raltegravir. Management: Avoid the use of oral / enteral aluminum hydroxide with raltegravir. No dose separation schedule has been established that adequately reduces the magnitude of interaction. Avoid combination

Calcium Carbonate: May decrease the serum concentration of Raltegravir. Consider therapy modification

Etravirine: May decrease the serum concentration of Raltegravir. Management: Concurrent use of etravirine with once-daily raltegravir (Isentress HD) is not recommended. Concurrent use of other raltegravir products with etravirine does not require any dose change. Monitor therapy

Fibric Acid Derivatives: Raltegravir may enhance the myopathic (rhabdomyolysis) effect of Fibric Acid Derivatives. Monitor therapy

Fosamprenavir: May decrease the serum concentration of Raltegravir. Raltegravir may decrease the serum concentration of Fosamprenavir. Consider therapy modification

HMG-CoA Reductase Inhibitors (Statins): Raltegravir may enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy

Magnesium Salts: May decrease the serum concentration of Raltegravir. Management: Avoid the use of oral / enteral magnesium salts with raltegravir. No dose separation schedule has been established that adequately reduces the magnitude of interaction. Avoid combination

Orlistat: May decrease the serum concentration of Antiretroviral Agents. Monitor therapy

Proton Pump Inhibitors: May increase the serum concentration of Raltegravir. Monitor therapy

Rifabutin: May decrease the serum concentration of Raltegravir. Specifically, minimum serum concentrations (Cmin) may be reduced. Total raltegravir exposure (i.e., AUC) may be increased. Monitor therapy

RifAMPin: May decrease the serum concentration of Raltegravir. Management: Increase raltegravir dose to 800 mg twice daily (adult dose) when used concomitantly with rifampin. Concurrent use of rifampin with once-daily raltegravir (Isentress HD) is not recommended. Consider therapy modification

Rifapentine: May increase the serum concentration of Raltegravir. Rifapentine may decrease the serum concentration of Raltegravir. Monitor therapy

Tipranavir: May decrease the serum concentration of Raltegravir. Management: Concurrent use of tipranavir/ritonavir with once-daily raltegravir (Isentress HD) is not recommended. Monitor therapy

Zidovudine: Raltegravir may enhance the myopathic (rhabdomyolysis) effect of Zidovudine. Monitor therapy

Adverse Reactions

>10%:

Hepatic: Increased serum ALT (1% to 11%; incidence higher with hepatitis B and/or C coinfection)

2% to 10%:

Central nervous system: Insomnia (4%), headache (2% to 4%), dizziness (2%), fatigue (2%)

Endocrine & metabolic: Increased serum glucose (126 to 250 mg/dL: 7% to 10%; 251 to 500 mg/dL: 2% to 3%)

Gastrointestinal: Increased serum lipase (2% to 5%), increased serum amylase (2% to 4%), nausea (3%)

Hematologic: Abnormal absolute neutrophil count (2% to 3%), thrombocytopenia (1% to 3%)

Hepatic: Increased serum AST (1% to 9%; incidence higher with hepatitis B and/or C coinfection), hyperbilirubinemia (<1% to 6%), increased serum alkaline phosphatase (<1% to 2%)

Neuromuscular & skeletal: Increased creatine phosphokinase (10 to 19.9 x ULN: 4%; ≥20 x ULN: 3%)

<2% (Limited to important or life-threatening): Anemia, cerebellar ataxia, depression (particularly in subjects with a pre-existing history of psychiatric illness), drug rash with eosinophilia and systemic symptoms (DRESS; Perry, 2013), gastritis, hepatic failure, hepatitis, hypersensitivity, myopathy, nephrolithiasis, psychomotor agitation (children; grade 3), renal failure, rhabdomyolysis, Stevens-Johnson syndrome, suicidal ideation, toxic epidermal necrolysis

Warnings/Precautions

Concerns related to adverse effects:

• Immune reconstitution syndrome: Patients may develop immune reconstitution syndrome resulting in the occurrence of an inflammatory response to an indolent or residual opportunistic infection during initial HIV treatment or activation of autoimmune disorders (eg, Graves’ disease, polymyositis, Guillain-Barré syndrome) later in therapy; further evaluation and treatment may be required.

• Myopathy: Grade 2 to 4 creatine kinase (CK) increases have been observed and myopathy and rhabdomyolysis have been reported; use caution in patients with a history of rhabdomyolysis, myopathy, or increased serum creatine kinase or who have risk factors for CK elevations and/or skeletal muscle abnormalities, including taking other drugs known to cause myopathy or rhabdomyolysis.

• Skin and hypersensitivity reactions: Severe, life-threatening or fatal cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. Hypersensitivity reactions (rash, constitutional symptoms, organ dysfunction) have also been reported. Discontinue immediately if a severe skin reaction or hypersensitivity symptoms develop. Monitor clinical status, including liver transaminases.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Chewable tablet: Contains phenylalanine.

• Tablets and oral suspension: Raltegravir film-coated tablets and chewable tablets or oral suspension are not bioequivalent and are not substitutable on a mg/mg basis.

Other warnings/precautions:

• Appropriate use: Raltegravir plus darunavir/ritonavir should not be used in adolescent and adult HIV-1 patients with a pre-ART CD4 count <200 cells/mm3 and/or HIV RNA >100,000 copies/mL (HHS [adult] 2016).

Monitoring Parameters

Viral load, CD4 count, signs of skin rash, signs/symptoms of depression and suicidal ideation

HIV occupational postexposure prophylaxis (PEP) (Kuhar, 2013): Documented HIV test (at baseline and 6 weeks, 12 weeks and 6 months after exposure); if confirmation that a fourth generation HIV p2 antigen-HIV antibody test is being used, monitor at baseline, 6 weeks and 4 months after exposure. CBC, renal and hepatic function assessments at baseline and 2 weeks after exposure (minimum recommendations, others dictated by clinical assessment)

Pregnancy Considerations

Raltegravir has high transfer across the human placenta and can be detected in neonatal serum after delivery. Data collected by the antiretroviral pregnancy registry are insufficient to evaluate human teratogenic risk. Maternal antiretroviral therapy may increase the risk of preterm delivery, although available information is conflicting possibly due to variability of maternal factors (disease severity; initiation of therapy); however, maternal antiretroviral medication should not be withheld due to concerns of preterm birth. Information related to stillbirth, low birth weight, and small for gestational age infants is limited. Long-term follow-up is recommended for all infants exposed to antiretroviral medications; children who develop significant organ system abnormalities of unknown etiology (particularly of the CNS or heart) should be evaluated for potential mitochondrial dysfunction.

Combination antiretroviral therapy (cART) therapy is recommended for all HIV-infected pregnant women to keep the viral load below the limit of detection and reduce the risk of perinatal transmission. When HIV is diagnosed during pregnancy in a woman who has never received antiretroviral therapy, cART should begin as soon as possible after diagnosis. The Health and Human Services (HHS) Perinatal HIV Guidelines consider raltegravir to be the preferred integrase inhibitor for initial use in antiretroviral-naive pregnant patients and is useful when drug interactions with protease inhibitors are a concern. Because of its ability to rapidly suppress viral load, raltegravir may be useful in women who present late in pregnancy with high viral loads. Dose adjustments are not required in pregnant women. In general, women who become pregnant on a stable cART regimen may continue that regimen if viral suppression is effective, appropriate drug exposure can be achieved, contraindications for use in pregnancy are not present, and the regimen is well tolerated. Monitoring during pregnancy is more frequent than in non-pregnant adults; cART should be continued postpartum. Reversible elevation of liver enzymes occurred in a patient who initiated raltegravir late in pregnancy; monitor liver enzymes if used during pregnancy.

For HIV-infected couples planning a pregnancy, maximum viral suppression with cART is recommended prior to conception for the HIV-infected partner(s) and expert consultation is recommended; modification of therapy (if needed) and optimization of the woman’s health should be done prior to conception. HIV-infected women not planning a pregnancy may use any available type of contraception, considering possible drug interactions and contraindications of the specific method. In addition, consistent use of condoms is also recommended (even during pregnancy) to prevent transmission of HIV or other sexually transmitted diseases.

Health care providers are encouraged to enroll pregnant women exposed to antiretroviral medications as early in pregnancy as possible in the Antiretroviral Pregnancy Registry (1-800-258-4263 or www.APRegistry.com). Health care providers caring for HIV-infected women and their infants may contact the National Perinatal HIV Hotline (888-448-8765) for clinical consultation (HHS [perinatal], 2016).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience insomnia, headache, dizziness, or nausea. Have patient report immediately to prescriber signs of infection, signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), muscle pain, joint pain, severe loss of strength and energy, muscle weakness, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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