Isentress
(raltegravir)Dosage & Administration
ISENTRESS and ISENTRESS HD can be administered with or without food .
Do not substitute ISENTRESS chewable tablets or ISENTRESS for oral suspension for the ISENTRESS 400 mg or 600 mg film-coated tablet.
See specific dosing guidance for chewable tablets and the formulation for oral suspension .
Adults
Pediatrics
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Isentress Prescribing Information
Adult Patients:
ISENTRESS® and ISENTRESS® HD are indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in adult patients.
Pediatric Patients:
ISENTRESS is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in pediatric patients weighing at least 2 kg.
ISENTRESS HD is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in pediatric patients weighing at least 40 kg.
General Dosing Recommendations
- Because the formulations have different pharmacokinetic profiles, do not substitute ISENTRESS chewable tablets or ISENTRESS for oral suspension for the ISENTRESS 400 mg film-coated tablet or the ISENTRESS HD 600 mg film-coated tablet. See specific dosing guidance for chewable tablets and the formulation for oral suspension.
- Because the extent to which ISENTRESS may be dialyzable is unknown, dosing before a dialysis session should be avoided [see Clinical Pharmacology (12.3)].
- ISENTRESS film-coated tablets must be swallowed whole.
- ISENTRESS chewable tablets may be chewed or swallowed whole. Maximum daily dose is 300 mg taken by mouth twice daily.
- For children who have difficulty chewing the 25 mg chewable tablet, the tablet may be crushed.
- Preparation of the crushed 25 mg chewable tablet:
- Place the tablet(s) in a small, clean cup. For each tablet, add a teaspoonful (~5 mL) of liquid (for example, water, juice, or breast milk).
- Within 2 minutes, the 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.
- Preparation of the crushed 25 mg chewable tablet:
- ISENTRESS for oral suspension:
- See Instructions for Use for details on preparation and administration of ISENTRESS for oral suspension.
- Using the provided mixing cup, combine 10 mL of water and the entire contents of one packet of ISENTRESS for oral suspension and mix. Each single-use packet for oral suspension contains 100 mg of raltegravir which is suspended in 10 mL of water giving a final concentration of 10 mg per mL. Maximum daily dose is 100 mg taken by mouth twice daily.
- Gently swirl the mixing cup for 45 seconds in a circular motion to mix the powder into a uniform suspension. Do not shake.
- Once mixed, measure the prescribed dose volume of suspension with a syringe and administer the dose orally. The dose should be administered orally within 30 minutes of mixing.
- Discard any remaining suspension into the trash.
Adults
The recommended adult dosage of ISENTRESS film-coated tablets is displayed in Table 1. ISENTRESS and ISENTRESS HD should be taken by mouth and may be taken with or without food [see Clinical Pharmacology (12.3)].
| Population | Recommended Dose |
|---|---|
| Treatment-naïve patients or patients who are virologically suppressed on an initial regimen of ISENTRESS 400 mg twice daily | 1200 mg (2 × 600 mg) once daily or 400 mg twice daily |
| Treatment-experienced | 400 mg twice daily |
| Treatment-naïve or treatment-experienced when coadministered with rifampin [see Drug Interactions (7.1)] | 800 mg (2 × 400 mg) twice daily |
Pediatrics
The recommended pediatric dosage of ISENTRESS is displayed in Table 2. ISENTRESS film-coated tablets, chewable tablets and for oral suspension should be taken by mouth and may be taken with or without food [see Clinical Pharmacology (12.3)].
| Recommended Pediatric Dosage and Formulation | ||||
|---|---|---|---|---|
| Population/Weight | Film-Coated Tablets 400 mg | Film-Coated Tablets 600 mg | Chewable Tablets 100 mg and 25 mg | For Oral Suspension 100 mg |
| ||||
If at least 40 kg and either:
| 400 mg twice daily | 1200 mg (2 × 600 mg) once daily | 300 mg twice daily (see Table 3) | NA |
| If at least 25 kg | 400 mg twice daily * | NA | Weight-based dosing twice daily (see Table 3) | NA |
| If at least 4 weeks of age and weighing 3 kg to less than 25 kg | NA | NA | Weight-based dosing twice daily (see Table 4) | Weight-based dosing twice daily up to 20 kg (see Table 4) |
| From birth to 4 weeks (28 days) weighing at least 2 kg | NA | NA | NA | Weight-based dosing once daily or twice daily (see Table 5) |
| Body Weight (kg) | Dose | Number of 100 mg Chewable Tablets |
|---|---|---|
| ||
| 25 to less than 28 | 150 mg twice daily | 1.5 × 100 mg † twice daily |
| 28 to less than 40 | 200 mg twice daily | 2 × 100 mg twice daily |
| At least 40 | 300 mg twice daily | 3 × 100 mg twice daily |
| Body Weight (kg) | Volume (Dose) of Suspension to be Administered | Number of Chewable Tablets † |
|---|---|---|
| ||
| 3 to less than 4 | 2.5 mL (25 mg) twice daily | 1 × 25 mg twice daily ‡ |
| 4 to less than 6 | 3 mL (30 mg) twice daily | |
| 6 to less than 8 | 4 mL (40 mg) twice daily | 2 × 25 mg twice daily ‡ |
| 8 to less than 10 | 6 mL (60 mg) twice daily | |
| 10 to less than 14 | 8 mL (80 mg) twice daily | 3 × 25 mg twice daily ‡ |
| 14 to less than 20 | 10 mL (100 mg) twice daily | 1 × 100 mg twice daily |
| 20 to less than 25 | Not applicable | 1.5 × 100 mg § twice daily |
- For full-term neonates (birth to 4 weeks [28 days] of age): Weight-based dosing of the oral suspension as specified in Table 5.
- No data are available in pre-term neonates. The use of ISENTRESS is not recommended in pre-term neonates.
| Body Weight (kg) | Volume (Dose) of Suspension to be Administered |
|---|---|
| Note: If the mother has taken ISENTRESS or ISENTRESS HD 2-24 hours before delivery, the neonate's first dose should be given between 24-48 hours after birth. | |
| |
| Birth to 1 Week - Once daily dosing * | |
| 2 to less than 3 | 0.4 mL (4 mg) once daily |
| 3 to less than 4 | 0.5 mL (5 mg) once daily |
| 4 to less than 5 | 0.7 mL (7 mg) once daily |
| 1 to 4 Weeks - Twice daily dosing † | |
| 2 to less than 3 | 0.8 mL (8 mg) twice daily |
| 3 to less than 4 | 1 mL (10 mg) twice daily |
| 4 to less than 5 | 1.5 mL (15 mg) twice daily |
- Film-coated Tablets
- 400 mg pink, oval-shaped, film-coated tablets with "227" on one side (ISENTRESS).
- 600 mg yellow, oval-shaped, film-coated tablets with corporate logo and "242" on one side and plain on the other side (ISENTRESS HD).
- Chewable Tablets
- 100 mg pale orange, oval-shaped, orange-banana flavored, chewable tablets scored on both sides and imprinted on one face with the corporate logo and "477" on opposite sides of the score.
- 25 mg pale yellow, round, orange-banana flavored, chewable tablets with the corporate logo on one side and "473" on the other side.
- For Oral Suspension
- 100 mg white to off-white, banana flavored, granular powder that may contain yellow or beige to tan particles in a child resistant single-use foil packet.
Pregnancy
Pregnancy Exposure Registry
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.
Risk Summary
Available data from the APR show no difference in the rate of overall birth defects for raltegravir compared to the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. Methodological limitations of the APR include the use of MACDP as the external comparator group. 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 (see Data).
In animal reproduction studies in rats and rabbits, no evidence of adverse developmental outcomes was observed with oral administration of raltegravir during organogenesis at doses that produced exposures up to approximately 4 times the maximum recommended human dose (MRHD) of 1200 mg (see Data).
Data
Human Data
Based on prospective reports from the APR of over 850 exposures to raltegravir during pregnancy resulting in live births (including over 450 exposures in the first trimester), there was no difference between the overall risk of birth defects for raltegravir compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of defects in live births was 3.1% (95% CI: 1.7% to 5.1%) following first trimester exposure to raltegravir-containing regimens and 3.7% (95% CI: 2.1% to 6.0%) following second and third trimester exposure to raltegravir-containing regimens.
There are limited data on the use of ISENTRESS 1200 mg (2 x 600 mg) once daily in pregnant women.
Animal Data
In a combined embryo/fetal and pre/postnatal development study, raltegravir was administered orally to rats at doses of 100, 300, 600 mg/kg/day on gestation day 6 to 20 or from gestation day 6 to lactation day 20. No effects on pre/postnatal development were observed up to the highest dose tested. Embryo-fetal findings were limited to an increase in the incidence of supernumerary ribs in the 600 mg/kg/day group. Systemic exposure (AUC) at 600 mg/kg/day was approximately 3 times higher than exposure at the MRHD of 1200 mg.
In pregnant rabbits, raltegravir was administered orally at doses of 100, 500, or 1000 mg/kg/day during the gestation days 7 to 20. No embryo/fetal effects were noted up to the highest dose of 1000 mg/kg/day. Systemic exposure (AUC) at 1000 mg/kg/day was approximately 4 times higher than exposures at the MRHD of 1200 mg. In both species, raltegravir has been shown to cross the placenta, with fetal plasma concentrations observed in rats approximately 1.5 to 2.5 times greater than in maternal plasma and fetal plasma concentrations in rabbits approximately 2% that of maternal concentrations on gestation day 20.
Lactation
Risk Summary
The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. There are no data on the presence of raltegravir in human milk, the effects on the breastfed infant, or the effects on milk production. When administered to lactating rats, raltegravir was present in milk (see Data). Because of the potential for: 1) HIV transmission (in HIV-negative infants), 2) developing viral resistance (in HIV-positive infants), and 3) adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving ISENTRESS/ISENTRESS HD.
Data
Raltegravir was excreted into the milk of lactating rats following oral administration (600 mg/kg/day) from gestation day 6 to lactation day 14, with milk concentrations approximately 3 times that of maternal plasma concentrations observed 2 hours postdose on lactation day 14.
Pediatric Use
ISENTRESS
HIV-1 Infected Children
The safety, tolerability, pharmacokinetic profile, and efficacy of twice daily ISENTRESS were evaluated in HIV-1 infected infants, children and adolescents 4 weeks to 18 years of age in an open-label, multicenter clinical trial, IMPAACT P1066 [see Dosage and Administration (2.3), Clinical Pharmacology (12.3) and Clinical Studies (14.4)]. The safety profile was comparable to that observed in adults [see Adverse Reactions (6.1)].
HIV-1 Exposed Neonates
The safety and pharmacokinetics of ISENTRESS for oral suspension were evaluated in 42 full-term HIV-1 exposed neonates at high risk of acquiring HIV-1 infection in a Phase 1, open-label, multicenter clinical study, IMPAACT P1110. Cohort 1 neonates received 2 single doses of ISENTRESS for oral suspension: the first within 48 hours of birth and the second at 7 to 10 days of age. Cohort 2 neonates received daily dosing of ISENTRESS for oral suspension for 6 weeks: 1.5 mg/kg once daily starting within 48 hours of birth through day 7 (week 1); 3 mg/kg twice daily on days 8 to 28 of age (weeks 2 to 4); and 6 mg/kg twice daily on days 29 to 42 of age (weeks 5 and 6). Sixteen neonates were enrolled in Cohort 1 (10 were exposed and 6 were unexposed to raltegravir in utero) and 26 in Cohort 2 (all unexposed to raltegravir in utero); all infants received a standard of care antiretroviral drug regimen for prevention of mother to child transmission. All enrolled neonates were followed for safety for a duration of 24 weeks. The 42 infants were 52% male, 69% Black and 12% Caucasian. HIV-1 status was assessed by nucleic acid test at birth, week 6 and week 24; all patients were HIV-1 negative at completion of the study. The safety profile was comparable to that observed in adults [see Adverse Reactions (6.1)].
ISENTRESS is not recommended in pre-term neonates or in pediatric patients weighing less than 2 kg.
ISENTRESS HD
ISENTRESS HD once daily has not been studied in pediatric patients. However population PK modeling and simulation support the use of 1200 mg (2 × 600 mg) once daily in pediatric patients weighing at least 40 kg [see Clinical Pharmacology (12.3)].
Geriatric Use
Clinical studies of ISENTRESS/ISENTRESS HD did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Use in Patients with Hepatic Impairment
No dosage adjustment of ISENTRESS is necessary for patients with mild to moderate (Child-Pugh A and B) hepatic impairment. No hepatic impairment study has been conducted with ISENTRESS HD and therefore administration in subjects with hepatic impairment is not recommended. The effect of severe hepatic impairment on the pharmacokinetics of raltegravir has not been studied [see Clinical Pharmacology (12.3)].
Use in Patients with Renal Impairment
No dosage adjustment of ISENTRESS or ISENTRESS HD is necessary in patients with any degree of renal impairment [see Clinical Pharmacology (12.3)]. The extent to which ISENTRESS may be dialyzable is unknown; therefore, dosing before a dialysis session should be avoided.
None
Severe Skin and Hypersensitivity Reactions
Severe, potentially life-threatening, and fatal skin reactions have been reported. These include cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hypersensitivity reactions have also been reported and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including hepatic failure. Discontinue ISENTRESS or ISENTRESS HD and other suspect agents immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (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, angioedema). Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated. Delay in stopping ISENTRESS or ISENTRESS HD treatment or other suspect agents after the onset of severe rash may result in a life-threatening reaction.
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including ISENTRESS. During the 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 (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.
Phenylketonurics
ISENTRESS Chewable Tablets contain phenylalanine, a component of aspartame. Each 25 mg ISENTRESS Chewable Tablet contains approximately 0.05 mg phenylalanine. Each 100 mg ISENTRESS Chewable Tablet contains approximately 0.10 mg phenylalanine. Phenylalanine can be harmful to patients with phenylketonuria.