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Raltegravir

Pronunciation

Pronunciation

(ral TEG ra vir)

Index Terms

  • MK-0518
  • RAL

Dosage Forms

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

Packet, Oral:

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

Tablet, Oral:

Isentress: 400 mg [contains polyethylene glycol]

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

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: 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: ~3 hours

Half-Life Elimination

~9 hours

Protein Binding

~83%

Special Populations: Renal Function Impairment

No clinically important pharmacokinetic differences were observed between subjects with severe renal impairment and healthy subjects. Because the extent to which raltegravir is dialyzable is unknown, avoid dosing before dialysis.

Special Populations: Hepatic Function Impairment

No clinically important pharmacokinetic differences were observed between subjects with moderate hepatic impairment and healthy subjects. Effect of severe hepatic impairment has not been studied.

Special Populations: Elderly

The effect of age on the pharmacokinetics of raltegravir was evaluated in the composite analysis. No dosage adjustment is necessary.

Special Populations: Children

The pharmacokinetic profile of raltegravir in children was similar to that observed in adults receiving 400 mg twice daily.

Special Populations: Gender

A study of the pharmacokinetics of raltegravir was performed in healthy adult men and women. Additionally, the effect of gender was evaluated in a composite analysis of pharmacokinetic data from 103 healthy subjects and 28 HIV-1 infected subjects receiving raltegravir monotherapy with fasted administration. No dosage adjustment is necessary.

Special Populations: Race

The effect of race on the pharmacokinetics of raltegravir was evaluated in the composite analysis. No dosage adjustment is necessary.

Use: Labeled Indications

HIV infection:

U.S. labeling: Treatment of HIV-1 infection in combination with other antiretroviral agents in patients 4 weeks and older and weighing at least 3 kg

Canadian labeling: Treatment of HIV-1 infection in combination with other antiretroviral agents in patients ≥2 years of age

Use: Unlabeled

Postexposure prophylaxis for occupational exposure to HIV

Contraindications

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

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

Dosage

HIV 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

U.S. labeling:

Infants ≥4 weeks and Children (≥3 to <25 kg): Weight-based dosing based on ~6 mg/kg/dose twice daily (maximum dose: 600 mg/day [chewable tablet]; 200 mg/day [oral suspension]).

3 to <4 kg: 20 mg twice daily (oral suspension)

4 to <6 kg: 30 mg twice daily (oral suspension)

6 to <8 kg: 40 mg twice daily (oral suspension)

8 to <11 kg: 60 mg twice daily (oral suspension)

11 to <14 kg: 80 mg twice daily (oral suspension) or 75 mg twice daily (chewable tablet) (see “Note”)

14 to <20 kg: 100 mg twice daily (oral suspension or chewable tablet) (see “Note”)

20 to <25 kg: 150 mg twice daily (chewable tablet)

Note: Infants and Children ≥4 weeks who are between 11 and <20 kg may use either the chewable tablet or the oral suspension. Patients can remain on the oral suspension as long as their weight is <20 kg.

Children and Adolescents ≥25 kg: Note: If unable to swallow a tablet, chewable tablets may be used.

Film-coated tablet: 400 mg twice daily.

Chewable tablet: Weight-based dosing based on ~6 mg/kg/dose twice daily (maximum dose: 600 mg daily).

25 to <28 kg: 150 mg twice daily (see "Note")

28 to <40 kg: 200 mg twice daily (see "Note")

≥40 kg: 300 mg twice daily (see "Note")

Note: May use either weight-based dosing (chewable tablet) or adult dosing (film-coated tablet).

Children and Adolescents weighing ≥25 kg, and Adults: Film-coated tablet: 400 mg twice daily. Raltegravir is a component of a recommended initial regimen with tenofovir plus emtricitabine (or lamivudine) in adolescent and adult ART-naive patients (HHS [adult] 2015).

Canadian labeling: Chewable tablet: Children 2 to <12 years (maximum dose: 600 mg/day):

7 to <10 kg: 50 mg twice daily

10 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

Occupational HIV postexposure, prophylaxis (off-label use): Adults: Oral: Film-coated tablet: 400 mg twice daily for 4 weeks with concomitant emtricitabine/tenofovir. Recommended as preferred therapy (Kuhar, 2013).

Dosage adjustment for rifampin coadministration: 800 mg twice daily. There are no data to guide dose adjustment in patients <18 years of age.

Dosage adjustment in 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.

Dosage adjustment in hepatic impairment:

Mild to moderate impairment: No dosage adjustment necessary.

Severe impairment: There are no dosage adjustments provided in manufacturer’s labeling (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: Open foil packet of drug (100 mg). Measure 5 mL water in provided mixing cup. Pour packet contents into 5 mL water, close lid and swirl for 30-60 seconds. Do not turn the mixing cup upside down. Once mixed, measure recommended suspension dose with an oral syringe. 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).

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

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

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. 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. 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 [may occur with fever, fatigue, malaise, conjunctivitis, or other constitutional symptoms], organ dysfunction and/or hepatic failure) have also been reported. Discontinue immediately if a severe skin reaction or hypersensitivity symptoms develop. Monitor liver transaminases and start supportive therapy.

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] 2015).

Monitoring Parameters

Viral load, CD4 count, lipid profile

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 Risk Factor

C

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies. Raltegravir has high transfer across the human placenta and can be detected in neonatal serum after delivery. Standard doses appear to be appropriate in pregnant women. The DHHS Perinatal HIV Guidelines consider raltegravir to be an alternative for use in antiretroviral-naïve pregnant patients when drug interactions with protease inhibitors are a concern. Because of its ability to rapidly suppress viral load, some experts have suggested using raltegravir in late pregnancy in women who have high viral loads; however, this use is not routinely recommended at this time. Reversible elevation of liver enzymes occurred in a patient who initiated raltegravir late in pregnancy; monitor liver enzymes if used during pregnancy.

Regardless of CD4 count or HIV RNA copy number, all HIV-infected pregnant women should receive a combination antiretroviral (ARV) drug regimen. A combination of antepartum, intrapartum, and infant ARV prophylaxis is recommended. ARV therapy should be started as soon as possible in women with symptomatic infection. Although earlier initiation may be more effective in reducing the perinatal transmission of HIV, initiation may be delayed until after 12 weeks gestation in women who do not require immediate treatment after careful consideration of maternal conditions (eg nausea and vomiting) and the potential risks of first trimester fetal exposure for specific agents. A scheduled cesarean delivery at 38 weeks gestation is recommended for all women with HIV RNA >1000 copies/mL or unknown concentrations near delivery in order to decrease transmission. If ARV therapy must be interrupted for <24 hours during the peripartum period, stop then restart all medications simultaneously in order to decrease the chance of developing resistance. Long-term follow-up is recommended for all infants exposed to ARV medications. In couples who want to conceive, the HIV-infected partner should attain maximum viral suppression prior to conception.

Health care providers are encouraged to enroll pregnant women exposed to antiretroviral medications 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], 2014).

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 dyspepsia. Have patient report immediately to prescriber signs of hepatic impairment, signs of renal impairment, myalgia, arthralgia, severe asthenia, ecchymosis, hemorrhaging, depression, suicidal ideation, signs of Stevens-Johnson syndrome/toxic epidermal necrolysis, or signs of infection (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 healthcare 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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