Raltegravir (Isentress) is an antiviral medicine that inhibits the integration of viral DNA in the human genome (DNA).

It is used to treat the following conditions:

• HIV-1 infection, treatment:

  • It is used in the treatment of HIV-1 infection in combination with other antiretroviral agents

• Off Label Usage of Raltegravir in Adults:

  • HIV-1 nonoccupational postexposure prophylaxis;

  • HIV-1 occupational postexposure prophylaxis

Isentress (Raltegravir) Dose in Adults

Isentress (Raltegravir) dosage in the treatment of HIV-1 infection:

• Isentress is recommended in combination with tenofovir plus emtricitabine (or lamivudine) in ART-naive patients in the initial treatment regimen.
• It 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/mm

• Treatment- naive patients:

  • Film-coated tablet:
    • 400 mg twice daily or 1,200 mg once daily given (2 x 600 mg tablet).
    • Patients virologically suppressed on an initial regimen of raltegravir 400 mg twice daily can be switched to 1,200 mg (2 x 600 mg tablet) once daily.
    • Once-daily dosing is not recommended for use during pregnancy

• Treatment- experienced patients:

  • Film-coated tablet:
    • 400 mg twice daily given.

Dose in the prophylaxis of HIV-1 nonoccupational postexposure (nPEP) (off-label):

• Oral: Film-coated tablet:

  • 400 mg twice daily given for 28 days in combination with other antiretroviral agents. Initiate therapy within 72 hours of exposure

Dose in the prophylaxis of HIV-1 occupational postexposure (oPEP) (off-label):

• Oral: Film-coated tablet:

  • 400 mg twice daily given for 4 weeks with concomitant emtricitabine/tenofovir.
  • Start therapy as soon as possible after occupational exposure (and within 72 hours) .

• Dosage adjustment for rifampin coadministration:

  • Treatment-naïve or treatment-experienced patients:
    • 800 mg twice daily given.

Isentress (Raltegravir) Dose in Childrens

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

Dose in the treatment of HIV-1 infection:

• Use in combination with other antiretrovirals (ARV) agents.

• Oral suspension (10 mg/mL): Infants and Children <20 kg:

  • Weight-based dosing:

    • 6 mg/kg/dose twice daily given
    • maximum dose is 100 mg/dose.
  • Fixed dosing:

    • 3 to <4 kg:

      • 25 mg twice daily given.

    • 4 to <6 kg:

      • 30 mg twice daily given.

    • 6 to <8 kg:

      • 40 mg twice daily given.

    • 8 to <11 kg:

      • 60 mg twice daily given.

    • 11 to <14 kg:

      • 80 mg twice daily given.

    • 14 to <20 kg:

      • 100 mg twice daily given.

  • Chewable tablets: Children weighing ≥11 kg:

    • Weight-based dosing:

      • 6 mg/kg/dose twice daily given
      • the maximum dose is 300 mg/dose.

    • Fixed dosing:

      • 11 to <14 kg:

        • 75 mg twice daily given.

      • 14 to <20 kg:

        • 100 mg twice daily given.

      • 20 to <28 kg:

        • 150 mg twice daily given.

      • 28 to <40 kg:

        • 200 mg twice daily given.

      • ≥40 kg:

        • 300 mg twice daily given.

    • Film-coated tablets: For patients able to swallow a tablet whole:

      • Isentress: 400 mg tablets: Children and Adolescents ≥25 kg:

        • 400 mg twice daily given.

      • Isentress HD: 600 mg tablets: Children and Adolescents ≥40 kg:

        • 1,200 mg is once daily given.

• The regimen is suitable for patients virologically suppressed on an initial regimen of raltegravir 400 mg twice daily.
• Although Isentress HD approved for weight ≥40 kg, current AIDSinfo guidelines do not recommend in patients weighing <50 kg due to insufficient data in efficacy trials.

Dose in the prophylaxis of HIV-1 nonoccupational postexposure (nPEP) (HHS [nPEP] 2016):

• Start therapy within 72 hours of exposure and continue for 28 days
• use in combination with other antiretroviral agents.

• Infants and Children <2 years:

  • Oral: Oral suspension (10 mg/mL): 6 mg/kg/dose twice daily given.

• Children ≥2 years: Oral:

  • Chewable tablets:

    • 11 to <14 kg:

      • 75 mg twice daily given.

    • 14 to <20 kg:

      • 100 mg twice daily given.

    • 20 to <28 kg:

      • 150 mg twice daily given.

    • 28 to <40 kg:

      • 200 mg twice daily given.

    • ≥40 kg:

      • 300 mg twice daily given.

  • Film-coated tablet: Isentress 400 mg tablet:

    • Children ≥6 years weighing >25 kg who are able to swallow a tablet whole:

      • 400 mg twice daily given.

    • Adolescents:

      • Oral: Film-coated tablet: Isentress 400 mg tablet:
      • 400 mg twice daily given for 28 days.

Dose in the prophylaxis of HIV-1 perinatal transmission, empiric therapy in neonates at high risk of transmission (3drug regimen) (HHS [perinatal] 2018):

• Dosing addresses completion of courses initiated at birth; if the neonate is diagnosed as HIV positive, stop empiric dosing and transition to a treatment regimen and monitoring.
• Recommended in combination with zidovudine and lamivudine for empiric treatment of HIV in neonates at higher risk of perinatal transmission.
• Duration of therapy is undefined
• some experts suggest a full 6 weeks of therapy, and others suggest that raltegravir can be discontinued once a negative nucleic acid test (NAT) is returned.

• Infants ≤6 weeks (GA ≥37 weeks and PNA 29 to 42 days):

  • Oral suspension (10 mg/mL): Oral:

  • Weight-based dosing:

    • 6 mg/kg/dose twice daily given.

  • Fixed dosing:

    • 3 to <4 kg: 25 mg twice daily given.
    • 4 to <6 kg: 30 mg twice daily given.

  • Dosing adjustment for concomitant rifampin therapy:

    • Pediatric-specific dosing recommendations are lacking.
    • In adult patients, raltegravir increased dosing adjustment suggested.

Raltegravir (Isentress) Pregnancy Risk Category: C

• Raltegravir is able to cross the human placenta.
• According to the data from the antiretroviral pregnancy registry, there has not been an increase in overall birth defects after the first trimester.
• Preterm births are more likely when maternal ART is used.
• Some studies have shown an increased risk of stillbirth, low birthweight, and small gestational age infants. However, not all studies have confirmed this.
• Maternal ART is beneficial and should be continued.
• All infants who have been exposed to antiretroviral medication should receive long-term monitoring.
• Children with significant organ system abnormalities (especially the heart or CNS) that are not of known etiology should be examined for possible mitochondrial dysfunction.
• The Health and Human Services (HHS) Perinatal HIV Guidelines consider raltegravir a preferred integrase strand transfer inhibitor (ISTI) for HIV-infected pregnant females who are antiretroviral-naive, who have had ART therapy in the past, who require a new ART regimen (due to poor tolerance or poor virologic response of current regimen), and who are not yet pregnant but are trying to conceive.
• Females who become pregnant while taking the raltegravir may continue to take the drug if they are well tolerated and effective in controlling viral infections.
• Raltegravir should not be used to treat acute infections during pregnancy.
• Raltegravir can be useful for patients with high viral loads in late pregnancy or drug interactions with protease inhibitors.
• Variable pharmacokinetics are possible with raltegravir.
• Pregnant patients do not need dose adjustments. However, once-daily dosing should be avoided until more pregnancy data are available.
• To keep HIV-positive pregnant women under the control and reduce the chance of perinatal transmission, it is generally recommended that ART be performed.
• Monitoring during pregnancy is easier than monitoring in adults who are not pregnant.
• All HIV-positive females should continue ART after birth. ART can also be modified after delivery.

Raltegravir (Isentress) use during breastfeeding:

• It is unknown if raltegravir can be found in breast milk.
• The risk of HIV transmission after birth does not disappear with infant or maternal antiretroviral treatment.
• The multiclass-resistant virus was also seen in infants who were breastfed despite the fact that they received maternal therapy.
• In the United States, where the infant formula is affordable, safe, and durable, and there is low risk of infant death from diarrhea or respiratory infections, women with HIV should not breastfeed in order to reduce the transmission of HIV.

Raltegravir (Isentress) dose in renal disease:

• Mild, moderate, and severe impairment:

  • No dosage adjustment required.

• End-stage renal disease (ESRD) on intermittent hemodialysis (IHD):

  • Dose after dialysis on dialysis days.

Raltegravir (Isentress) dose in Liver disease:

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

  • Mild-to-moderate impairment:

    • No dosage adjustment required.

  • Severe impairment:

    • There are no dosage adjustments given in the manufacturer’s labeling (has not been studied).

  • Film-coated tablet (600 mg formulation):

    • Use is not advised (has not been studied).

Common Side Effects of Raltegravir (Isentress) Include:

• Hepatic:

  • Increased Serum ALT

Less Common Side Effects Of Raltegravir (Isentress) Include:

• Central Nervous System:

  • Headache
  • Insomnia
  • Abnormal Dreams
  • Nightmares
  • Dizziness
  • Fatigue
  • Depression
  • Suicidal Ideation
  • Suicidal Tendencies
  • Psychomotor Agitation
  • Abnormal Behavior

• Dermatologic:

  • Allergic Rash

• Endocrine & Metabolic:

  • Increased Serum Glucose

• Gastrointestinal:

  • Increased Serum Lipase
  • Increased Serum Amylase
  • Nausea
  • Decreased Appetite
  • Diarrhea
  • Flatulence
  • Abdominal Pain
  • Dyspepsia
  • Gastritis
  • Vomiting

• Genitourinary:

  • Herpes Genitalis

• Hematologic & Oncologic:

  • Decrease In Absolute Neutrophil Count
  • Thrombocytopenia
  • Decreased Hemoglobin

• Hepatic:

  • Increased Serum AST
  • Hyperbilirubinemia
  • Increased Serum Alkaline Phosphatase
  • Hepatitis

• Hypersensitivity:

  • Hypersensitivity Reaction

• Infection:

  • Herpes Zoster

• Neuromuscular & Skeletal:

  • Increased Creatine Phosphokinase
  • Weakness

• Renal:

  • Nephrolithiasis
  • Renal Failure
  • Increased Serum Creatinine

Rare Side effects of Raltegravir (Isentress):

• Hematologic & Oncologic:

  • Malignant Neoplasm

• Neuromuscular & Skeletal:

  • Myopathy
  • Rhabdomyolysis

Contraindication to Raltegravir (Isentress) Include:

• Hypersensitivity to raltegravir and any other component of the formulation

Warnings and precautions

• Immune reconstitution syndrome:

  • Some patients may develop an immune reconstitution syndrome.
  • This is a condition that results in an inflammatory response to an indolent, residual opportunistic HIV infection, activation of autoimmune disorders such as Graves' disease, Guillain Barre syndrome, or polymyositis, later in therapy.
  • Further evaluation and treatment may be necessary.

• Myopathy

  • There have been reports of myopathy and rhabdomyolysis, as well as grade 2 to 4 increases in creatine kinase.
  • Patients with a history rhabdomyolysis or myopathy, increased serum creatine kinase, or risk factors for CK elevations or skeletal muscle abnormalities (including those who are taking any other drugs that can cause myopathy or rhabdomyolysis) should be cautious.

• Hypersensitivity and skin reactions

  • Stevens-Johnson syndrome, toxic epidermal necrolysis and other severe cases have been reported.
  • Hypersensitivity reactions (rash and constitutional symptoms, or organ dysfunction) are also common.
  • If you experience severe skin reactions or hypersensitivity, please stop immediately.
  • Monitor your clinical status, including liver transaminases.

Raltegravir: Drug Interaction

Monitor:

• Viral load
• CD4 count
• signs of skin rash
• signs/symptoms of depression and suicidal ideation HIV occupational postexposure prophylaxis
• Documented HIV test (at baseline and 6 weeks, 12 weeks and 6 months after exposure)
• monitor at baseline, 6 weeks and 4 months after exposure if confirmation that a fourth-generation HIV p2 antigen-HIV antibody test is being used, .
• CBC, renal functions and liver function assessments at baseline and 2 weeks after exposure.

How to administer Raltegravir (Isentress)?

• May be given without regard to meals.

Chewable tablets:

• May be chewed or swallowed whole
• the chewable 100 mg tablet can be divided into two halves.

Film-coated tablets:

• Must be swallowed as a whole.

Oral suspension:

• Pour the packet contents into 10 mL of water using the cup provided.
• close lid and swirl in a circular motion for 45 seconds
• do not shake.
• Do not turn the mixing cup upside down.
• Once mixed, measure the recommended suspension dose with an oral syringe (concentration of suspension is 10 mg/mL).
• Give within 30 minutes of mixing with water.
• Discard any remaining suspension in the trash.

Mechanism of action of Raltegravir (Isentress):

• Reverse transcriptase produces a viral cDNA strand that is then processed and inserted into human genomes by HIV-1 integrase, encoded by the pol gene.
• Raltegravir blocks the catalytic activity and prevents the integration of proviral genes into human DNA.
• Pediatric patients had a similar pharmacokinetic profile to adults.

Absorption: Film-coated tablet (400 mg formulation):

• AUC increased twofold with a high-fat meal

• Chewable tablet:

  • AUC decreased by almost 6% with a high-fat meal (not clinically significant)

• Oral suspension:

  • The effect of food is not studied

Protein binding:

• almost 83%

Metabolism:

• mainly hepatic glucuronidation mediated by UGT1A1

Bioavailability:

• 600 mg film-coated tablet, chewable tablet, and oral suspension have higher bioavailability compared to 400 mg film-coated tablet; dosage forms are not interchangeable.

Half-life elimination:

• ~9 hours

Time to peak, plasma:

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

Excretion:

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

International Brands of Raltegravir:

• Isentress
• Isentress HD

Isentress (Raltegravir) Brands in Pakistan

No Brands Available in Pakistan.