raltegravir (Rx)

>10% (STARMARK trial)

Serum alanine aminotransferase, Grade 2-4 (2-11%)

Serum aspartate aminotransferase, Grade 2-4 (1-8%)

1-10% (STARTMRK trial)

Fasting serum glucose test, Grade 2-4 (7%)

Total serum bilirubin, Grade 2-4 (≤5%)

Headache (4%)

Insomnia (4%)

Nausea (3%)

ANC, Grade 2-4 (1-3%)

Serum alkaline phosphate, Grade 2-4 (≤3%)

Dizziness (2%) Fatigue (2%)

Creatinine (≤1%)

Hemoglobin, Grade 2-4 (≤1%)

Platelet count, Grade 2-3 (≤1%)

1-10% (ONCEMRK trial)

Lipase, Grade 2-4 (≤2-7%)

Creatine kinase, Grade 2-4 (≤2-4%)

Serum aspartate aminotransferase, Grade 2-4 (≤5%)

Serum alanine aminotransferase, Grade 2-4 (≤4%)

Serum alkaline phosphate, Grade 2-4 (≤1%)

ANC, Grade 2-4 (≤2%)

Platelet count, Grade 2-3 (≤1%)

Total serum bilirubin, Grade 2-4 (≤3%)

Headache (1%)

Nausea (1%)

Postmarketing Reports

Blood and lymphatic system disorders: Thrombocytopenia

Gastrointestinal Disorders: Diarrhea

Hepatobiliary disorders: Hepatic failure (with and without associated hypersensitivity) in patients with underlying liver disease and/or concomitant medications

Musculoskeletal and connective tissue disorders: Rhabdomyolysis

Nervous system disorders: Cerebellar ataxia

Contraindications

None

Cautions

Risk of immune reconstitution syndrome if used with HAART; during initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, tuberculosis), which may necessitate further evaluation and treatment

Autoimmune disorders (eg, Graves disease, polymyositis, Guillain-Barré syndrome) reported in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment

Concomitant medications known to increase risk of myopathy or rhabdomyolysis

Coadministration with drugs that are strong inducers of UGT1A1 may result in reduced plasma concentrations of raltegravir

Drug rash with eosinophilia and systemic symptoms (DRESS) reported

Severe, potentially life-threatening and fatal skin reactions reported; skin reactions include cases of Stevens-Johnson syndrome, hypersensitivity reaction and toxic epidermal necrolysis; immediately discontinue treatment if severe hypersensitivity, severe rash, or rash with systemic symptoms or liver aminotransferase elevations develops and monitor clinical status, including liver aminotransferases closely

Chewable tablets contain phenylalanine, a component of aspartame; phenylalanine can be harmful to patients with phenylketonuria

Drug interactions overview

• Coadministration of raltegravir with drugs that inhibit UGT1A1 (eg, rifampin) may reduce plasma levels of raltegravir (see Dosage Modifications)
• Coadministration with other strong inducers (eg, carbamazepine, phenobarbital, phenytoin) of drug-metabolizing enzymes on raltegravir is unknown and therefore not recommended

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women; healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1- 800-258-4263

Available data from APR show no difference in rate of overall birth defects for raltegravir compared to background rate for major birth defects of 2.7% in U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP); the rate of miscarriage is not reported in the APR; the MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation

In animal reproduction studies in rats and rabbits, no evidence of adverse developmental outcomes observed with oral administration during organogenesis at doses that produced exposures up to approximately 4 times maximal recommended human dose (MRHD) of 1200 mg

Lactation

The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers in United States not breastfeed infants to avoid risking postnatal transmission of HIV-1 infection

No data are available on presence of raltegravir in human milk, effects on breastfed infant, or on milk production; when administered to lactating rats, raltegravir was present in milk

Owing to the potential for HIV transmission (in HIV-negative infants), developing viral resistance (in HIV- positive infants), and adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving therapy

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Inhibits catalytic activity of HIV-1 integrase, an HIV encoded enzyme required for viral replication

Absorption

Fasted state

• Peak plasma concentration: 4.5 mcg/mL (400 mg PO BID and 1200 mg PO qDay)
• Peak plasma time: ~3 hr (400 mg PO BID)
• Peak plasma time: ~1.5 – 2 hr (1200 mg PO qDay)
• Steady state: 2 days

Effect of food

• Low fat

  • AUC ratio: 0.54 (400 mg PO BID); 0.58 (1200 mg PO BID)
  • Peak plasma concentration ratio: 0.48 (400 mg PO BID); 0.48 (1200 mg PO qDay)

• Moderate fat

  • AUC ratio: 1.13 (400 mg PO BID)
  • Peak plasma concentration ratio: 1.05 (400 mg PO BID)

• High fat

  • AUC ratio: 2.11 (400 mg PO BID); 1.02 (1200 mg PO BID); 0.94 (chewable tablet)
  • Peak plasma concentration ratio: 1.96 (400 mg PO BID); 0.72 (1200 mg PO qDay); 0.38 (chewable tablet)

Distribution

Protein Bound: ~83%

Metabolism

Primarily metabolized by UGT1A1-mediated glucuronidation

Elimination

Half-Life: ~9 hr

Excretion: 51% (feces); 32% (urine)

Oral Suspension Preparation

Combine and mix 10 mL of water and 1 packet (100 mg) of the oral suspension

Gently swirl mixing cup for 45 seconds in a circular motion to mix powder into a uniform suspension; final concentration (10 mg/mL); do not shake

Once mixed, measure prescribed dose volume with a syringe and administer the dose orally

Administer dose within 30 minutes of mixing

Discard any remaining suspension into the trash

Oral Administration

May administer with or without food

Do not substitute chewable tablets or oral suspension for film-coated tablets; these are not bioequivalent, and therefore, are not interchangeable

Film-coated tablet: Must be swallowed whole

Chewable tablet

• May be chewed or swallowed whole

• Preparation of crushed 25-mg chewable tablets for patients who difficulty chewing tablets

  • Place tablet(s) in a small, clean cup
  • For each tablet, add a teaspoonful (~5 mL) of liquid (eg, water, juice, breast milk)
  • Within 2 minutes, tablet(s) will absorb the liquid and fall apart
  • Using a spoon, crush any remaining pieces of the tablet(s)
  • Immediately administer the entire dose orally
  • If any portion of the dose is left in the cup, add another teaspoonful (~5 mL) of liquid, swirl and administer immediately

Storage

Oral suspension

• Store at room temperature between 68-77ºF (20-25ºC)
• Store in the original container
• Do not open foil packet until ready for use

Chewable tablets

• Store at room temperature between 68-77°F (20-25°C)
• Store in the original package with the bottle tightly closed
• Keep the drying agent (desiccant) in bottle to protect from moisture

Film-coated tablets

• Store at room temperature between 68-77°F (20-25°C)
• Store in the original package with the bottle tightly closed
• Keep the drying agent (desiccant) in bottle to protect from moisture