Drug Safety-related Labeling Changes (SrLC)

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ISENTRESS (NDA-022145)

(RALTEGRAVIR POTASSIUM)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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05/18/2021 (SUPPL-44)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined

…

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.

…

07/14/2020 (SUPPL-42)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.7       Use in Patients with Renal Impairment

(Additions and/or revisions underlined)

No dosage adjustment of ISENTRESS or ISENTRESS HD is necessary in patients with any degree of renal impairment. The extent to which ISENTRESS may be dialyzable is unknown, therefore, dosing before a dialysis session should be avoided.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Chewable Tablets

Inform parents and/or caregivers that the chewable tablets can be chewed or swallowed whole. Additionally, the 25 mg chewable tablet may be crushed. Instruct parents and/or caregivers that ISENTRESS 25 mg chewable tablets, if crushed, should be administered immediately.

03/05/2018 (SUPPL-38)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions underlined)

…

ONCEMRK (ISENTRESS HD 1200 mg [2 x 600 mg] once daily)

In ONCEMRK, subjects received ISENTRESS HD 1200 mg once daily (n=531) or ISENTRESS 400 mg twice daily (n=266) both in combination with emtricitabine (+) tenofovir disoproxil fumarate. During double-blind treatment, the total follow-up for subjects with ISENTRESS HD 1200 mg once daily was 913 patient-years and for ISENTRESS 400 mg twice daily was 450 patient-years.

In ONCEMRK, the rate of discontinuation of therapy due to adverse events through Week 96 was 1% in subjects receiving ISENTRESS HD 1200 mg (2 x 600 mg) once daily and 2% in subjects receiving ISENTRESS 400 mg twice daily.

Clinical adverse reactions of moderate to severe intensity occurring in greater than or equal to 2% of treatment-naïve subjects treated with ISENTRESS 400 mg twice daily or efavirenz in STARTMRK through Week 240 or ISENTRESS HD 1200 mg once daily or ISENTRESS 400 mg twice daily in ONCEMRK through Week 96 are presented in Table 6.

In STARTMRK, clinical adverse reactions of all intensities (mild, moderate and severe) occurring in

greater than or equal to 2% of subjects on ISENTRESS 400 mg twice daily through Week 240 also include diarrhea, flatulence, asthenia, decreased appetite, abnormal dreams, depression and nightmare. In ONCEMRK, clinical adverse reactions of all intensities (mild, moderate and severe) occurring in greater than or equal to 2% of subjects on ISENTRESS HD or ISENTRESS 400 mg twice daily through Week 96 also include abdominal pain, diarrhea, vomiting, and decreased appetite.

…

At 96 weeks, in treatment-naïve subjects receiving ISENTRESS HD 1200 mg (2 x 600 mg) once daily, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 27%, 40% and 13%, respectively, of co-infected subjects treated with ISENTRESS HD 1200 mg once daily as compared to 7%, 5% and 3% of all other subjects treated with ISENTRESS HD 1200 mg once daily.

…

7 Drug Interactions

7.2 Drugs without Clinically Significant Interactions with ISENTRESS or ISENTRESS HD

(additions underlined)

ISENTRESS

…

There is no predicted pharmacokinetic drug interaction between ISENTRESS and tenofovir alafenamide.

ISENTRESS HD

…

There is no predicted pharmacokinetic drug interaction between ISENTRESS HD and tenofovir alafenamide.

8 Use in Specific Populations

8.1 Pregnancy

(additions underlined)

…

Data

 Human Data

Based on prospective reports from the APR of over 500 exposures to raltegravir during pregnancy resulting in live births (including over 250 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 2.9% (95% CI: 1.2% to 5.6%) following first trimester exposure to raltegravir-containing regimens and 3.6% (95% CI: 1.6% to 6.6%) following second and third trimester exposure to raltegravir-containing regimens.

…

11/22/2017 (SUPPL-37)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

HIV-1 Exposed Neonates

Forty-two neonates were treated with ISENTRESS for up to 6 weeks from birth, and followed for a total of 24 weeks in IMPAACT P1110. There were no drug related clinical adverse reactions and three drug-related laboratory adverse reactions (one case of transient Grade 4 neutropenia in a subject receiving zidovudine-containing regimen for prevention of mother to child transmission (PMTCT), and two bilirubin elevations (one each, Grade 1 and Grade 2) considered non- serious and not requiring specific therapy). The safety profile in neonates was generally similar to that observed in older patients treated with ISENTRESS. No clinically meaningful differences in the adverse event profile of neonates were observed when compared to adults.

8 Use in Specific Populations

8.4 Pediatric Use ISENTRESS

(Newly revised subsections title; additions and/or revisions are underlined)

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…

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.

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…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION ISENTRESS (raltegravir) film-coated tablets ISENTRESS (raltegravir) chewable tablets ISENTRESS HD (raltegravir) film-coated tablets ISENTRESS (raltegravir) for oral suspension

(Extensive changes; please refer to label)

05/26/2017 (SUPPL-36)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Severe Skin and Hypersensitivity Reactions

(Additions and/or revisions are underlined)

…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.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

Treatment-Naïve Adults

The safety of ISENTRESS was evaluated in HIV-infected treatment-naïve subjects in 2 Phase III studies: STARTMRK evaluated ISENTRESS 400 mg twice daily versus efavirenz, both in combination with emtricitabine (+) tenofovir disoproxil fumarate (TDF), and ONCEMRK evaluated ISENTRESS HD 1200 mg (2 x 600 mg) once daily versus ISENTRESS 400 mg twice daily, both in combination with emtricitabine (+) tenofovir disoproxil fumarate. Safety data from these two studies are presented side-by- side in Tables 5 and 6 to simplify presentation; direct comparisons across trials should not be made due to differing duration of follow-up and study design.

STARTMRK (ISENTRESS 400 mg twice daily)

In STARTMRK, subjects received ISENTRESS 400 mg twice daily (N=281) or efavirenz (EFV) 600 mg at bedtime (N=282) both in combination with emtricitabine (+) tenofovir disoproxil fumarate, (N=282). During double-blind treatment, the total follow-up for subjects receiving ISENTRESS 400 mg twice daily + emtricitabine (+) tenofovir disoproxil fumarate was 1104 patient-years and 1036 patient-years for subjects receiving efavirenz 600 mg at bedtime + emtricitabine (+) tenofovir disoproxil fumarate.

In STARTMRK, the rate of discontinuation of therapy due to adverse events through Week 240 was 5% in subjects receiving ISENTRESS + emtricitabine (+) tenofovir disoproxil fumarate and 10% in subjects receiving efavirenz + emtricitabine (+) tenofovir disoproxil fumarate.

ONCEMRK (ISENTRESS HD 1200 mg [2 x 600 mg] once daily)

In ONCEMRK, subjects received ISENTRESS HD 1200 mg once daily (n=531) or ISENTRESS 400 mg twice daily (n=266) both in combination with emtricitabine (+) tenofovir disoproxil fumarate. During double-blind treatment, the total follow-up for subjects with ISENTRESS HD 1200 mg once daily was 516 patient-years and for ISENTRESS 400 mg twice daily was 258 patient-years.

In ONCEMRK, the rate of discontinuation of therapy due to adverse events through Week 48 was 1% in subjects receiving ISENTRESS HD 1200 mg (2 x 600 mg) once daily and 2% in subjects receiving ISENTRESS 400 mg twice daily.

Clinical adverse reactions of moderate to severe intensity occurring in greater than or equal to 2% of treatment-naïve subjects treated with ISENTRESS 400 mg twice daily or efavirenz in STARTMRK through Week 240 or ISENTRESS HD 1200 mg once daily or ISENTRESS 400 mg twice daily in ONCEMRK through Week 48 are presented in Table 5.

In STARTMRK, clinical adverse reactions of all intensities (mild, moderate and severe) occurring in

Greater than or equal to 2% of subjects on ISENTRESS 400 mg twice daily through Week 240 also include diarrhea, flatulence, asthenia, decreased appetite, abnormal dreams, depression and nightmare. In ONCEMRK, clinical adverse reactions of all intensities (mild, moderate and severe) occurring in greater than or equal to 2% of subjects on ISENTRESS HD or ISENTRESS 400 mg twice daily through Week 48 also include abdominal pain, diarrhea, vomiting, and decreased appetite.

 

Table 5: Adverse Reactions* of Moderate to Severe Intensity† Occurring in Greater than or Equal to 2% of Treatment-Naïve Adult Subjects Receiving ISENTRESS and ISENTRESS HD (Table has been revised; please refer to label)

 

Laboratory Abnormalities

The percentages of adult subjects with selected Grade 2 to 4 laboratory abnormalities (that represent a worsening Grade from baseline) who were treated with ISENTRESS 400 mg twice daily or efavirenz in STARTMRK or ISENTRESS HD 1200 mg once daily or ISENTRESS 400 mg twice daily in ONCEMRK are presented in Table 6.

 

Table 6: Selected Grade 2 to 4 Laboratory Abnormalities Reported in Treatment-Naïve Subjects (Table has been revised; please refer to label)

 

Lipids, Change from Baseline

Changes from baseline in fasting lipids are shown in Table 7.

Table 7: Lipid Values, Mean Change from Baseline, STARTMRK Study (Table has been revised; please refer to label)

 

Treatment-Experienced Adults

…Clinical ADRs of moderate to severe intensity occurring in greater than or equal to 2% of subjects treated with ISENTRESS and occurring at a higher rate compared to placebo are presented in Table 8.

Table 8: Adverse Drug Reactions* of Moderate to Severe Intensity Occurring in Greater than or Equal to 2% of Treatment-Experienced Adult Subjects Receiving ISENTRESS and at a Higher Rate Compared to Placebo (96 Week Analysis) (Table has been revised; please refer to label)

Laboratory Abnormalities

The percentages of adult subjects treated with ISENTRESS 400 mg twice daily or placebo in Studies BENCHMRK 1 and BENCHMRK 2 with selected Grade 2 to 4 laboratory abnormalities representing a worsening Grade from baseline are presented in Table 9.

Table 9: Selected Grade 2 to 4 Laboratory Abnormalities Reported in Treatment-Experienced Subjects (96 Week Analysis) (Table has been revised; please refer to label)

 

Less Common Adverse Reactions Observed in Treatment-Naïve and Treatment-Experienced Studies

The following ADRs occurred in <2% of treatment-naïve or treatment-experienced subjects receiving ISENTRESS or ISENTRESS HD in a combination regimen.

 

Selected Adverse Events - Adults

In studies of ISENTRESS 400 mg twice daily, cancers were reported in treatment-experienced subjects who initiated ISENTRESS or placebo, both with OBT, and in treatment-naïve subjects who initiated ISENTRESS or efavirenz, both with emtricitabine (+) tenofovir disoproxil fumarate; several were recurrent…

Grade 2-4 creatine kinase laboratory abnormalities were observed in subjects treated with ISENTRESS and ISENTRESS HD (see Tables 6 and 8). Myopathy and rhabdomyolysis have been reported with ISENTRESS…

 

Patients with Co-existing Conditions - Adults

Patients Co-infected with Hepatitis B and/or Hepatitis C Virus

In Phase III studies of ISENTRESS, patients with chronic (but not acute) active hepatitis B and/or hepatitis C virus co-infection were permitted to enroll provided that baseline liver function tests did not exceed 5 times the upper limit of normal (ULN). In the treatment-experienced studies, BENCHMRK 1 and BENCHMRK 2, 16% of all patients (114/699) were co-infected; in the treatment-naïve studies, STARTMRK and ONCEMRK, 6% (34/563) and 3% (23/797), respectively, were co-infected…

At 96 weeks, in treatment-experienced subjects receiving ISENTRESS 400 mg twice daily, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 29%, 34% and 13%, respectively, of co-infected subjects treated with ISENTRESS as compared to 11%, 10% and 9% of all other subjects treated with ISENTRESS. At 240 weeks, in treatment-naïve subjects receiving ISENTRESS 400 mg twice daily, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 22%, 44% and 17%, respectively, of co-infected subjects treated with ISENTRESS as compared to 13%, 13% and 5% of all other subjects treated with ISENTRESS.

At 48 weeks, in treatment-naïve subjects receiving ISENTRESS HD 1200 mg (2 x 600 mg) once daily, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 13%, 33% and 13%, respectively, of co-infected subjects treated with ISENTRESS HD 1200 mg once daily as compared to 4%, 3% and 2% of all other subjects treated with ISENTRESS HD 1200 mg once daily.

7 Drug Interactions

7.1 Effect of Other Agents on the Pharmacokinetics of Raltegravir

(Additions and/or revisions are underlined)

…

Selected drug interactions are presented in Table 10. In some cases, recommendations differ for ISENTRESS versus ISENTRESS HD.

Table 10: Selected Drug Interactions in Adults (Table has been revised; please refer to label)

7.2 Drugs without Clinically Significant Interactions with ISENTRESS or ISENTRESS HD

(Additions and/or revisions are underlined)

ISENTRESS

In drug interaction studies performed using ISENTRESS film-coated tablets 400 mg twice daily dose, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of the following: ethinyl estradiol/norgestimate, methadone,  midazolam,  lamivudine, tenofovir disoproxil fumarate,  etravirine, darunavir/ritonavir, or boceprevir. Moreover, atazanavir, atazanavir/ritonavir, boceprevir, calcium carbonate antacids, darunavir/ritonavir, efavirenz, etravirine, omeprazole, or tipranavir/ritonavir did not have a clinically meaningful effect on the pharmacokinetics of 400 mg twice daily raltegravir. No dose adjustment is required when ISENTRESS 400 mg twice daily is coadministered with these drugs.

ISENTRESS HD

In drug interaction studies, efavirenz did not have a clinically meaningful effect on the pharmacokinetics of ISENTRESS HD 1200 mg (2 x 600 mg) once daily. No dose adjustment is recommended when ISENTRESS HD 1200 mg once daily is coadministered with atazanavir, atazanavir/ritonavir, hormonal contraceptives, methadone, lamivudine, tenofovir disoproxil fumarate, darunavir/ritonavir, boceprevir, efavirenz and omeprazole.

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

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.

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 maximal recommended human dose (MRHD) of 1200 mg.

 

Data

Human Data

Based on prospective reports from the APR of over 400 exposures to raltegravir during pregnancy resulting in live births (including over 200 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 2.8% (95% CI: 1.1% to 5.8%) following first trimester exposure to raltegravir-containing regimens and 3.4% (95% CI: 1.5% to 6.6%) following second and third trimester exposure to raltegravir-containing regimens.

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 exposures (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.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

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. 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.

8.4 Pediatric Use

(Additions and/or revisions are underlined)

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…

ISENTRESS HD once daily has not been studied in pediatric patients. However population PK modeling and simulation support the use of 1200 mg (2 x 600 mg) once daily in pediatric patients weighing at least 40 kg.

8.5 Geriatric Use

(Additions and/or revisions are underlined)

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…

8.6 Use in Patients with Hepatic Impairment

(Additions and/or revisions are underlined)

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…

8.7 Use in Patients with Renal Impairment

(Additions and/or revisions are underlined)

No dosage adjustment of ISENTRESS or ISENTRESS HD is necessary in patients with any degree of renal impairment. The extent to which ISENTRESS may be dialyzable is unknown.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Severe and Potentially Life-threatening Rash

Inform patients that severe and potentially life-threatening rash has been reported. Advise patients to immediately contact their healthcare provider if they develop rash. Instruct patients to immediately stop taking ISENTRESS or ISENTRESS HD and other suspect agents,…

Immune Reconstitution Syndrome

Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started.

Rhabdomyolysis

Before patients begin ISENTRESS or ISENTRESS HD, ask them if they have a history of rhabdomyolysis, myopathy or increased creatine kinase or if they are taking medications known to cause these conditions such as statins, fenofibrate, gemfibrozil or zidovudine.

Drug Interactions

Inform patients that ISENTRESS or ISENTRESS HD may interact with some drugs and ask them to identify all their current medications including over-the-counter agents.

Missed Dosage

Inform patients that it is important to take ISENTRESS or ISENTRESS HD on a regular dosing schedule as instructed by their healthcare provider and to avoid missing doses as it can result in development of resistance.

Pregnancy Registry

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ISENTRESS or ISENTRESS HD during pregnancy.

Lactation

Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk.

PATIENT INFORMATION

(Additions and/or revisions are underlined)

What are ISENTRESS and ISENTRESS HD?

…

ISENTRESS HD is a prescription HIV medicine used with other antiretroviral medicines to treat HIV-1 infection in adults, and in children weighing at least 88 pounds (40 kg).

…

Before you take ISENTRESS or ISENTRESS HD, tell your healthcare provider about all of your medical conditions, including if you:

• receive kidney dialysis treatment

• are pregnant or plan to become pregnant. It is not known if ISENTRESS or ISENTRESS HD can harm your unborn baby.

• are breastfeeding or plan to breastfeed. Do not breastfeed if you take ISENTRESS or ISENTRESS HD.

  • It is not known if ISENTRESS or ISENTRESS HD can pass into your breast milk.

…Some medicines interact with ISENTRESS and ISENTRESS HD.

• You can ask your healthcare provider or pharmacist for a list of medicines that interact with ISENTRESS and ISENTRESS HD.

• Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take ISENTRESS or ISENTRESS HD with other medicines.

How should I take ISENTRESS or ISENTRESS HD?

• Take ISENTRESS or ISENTRESS HD exactly as prescribed by your healthcare provider.

• Do not change your dose of ISENTRESS or ISENTRESS HD or stop your treatment without talking with your healthcare provider first.

• Stay under the care of your healthcare provider during treatment with ISENTRESS or ISENTRESS HD.

• ISENTRESS film-coated tablets and ISENTRESS HD film-coated tablets must be swallowed whole.

• Do not switch between the ISENTRESS 400 mg film-coated tablet and the ISENTRESS HD 600 mg film-coated tablet if your prescribed dose is 1200 mg.

• Do not run out of ISENTRESS or ISENTRESS HD. The virus in your blood may increase and the virus may become harder to treat. Get a refill of your ISENTRESS or ISENTRESS HD from your healthcare provider or pharmacy before you run out.

• Take ISENTRESS or ISENTRESS HD on a regular dosing schedule as instructed by your healthcare provider. Do not miss doses.

• If you take too much ISENTRESS or ISENTRESS HD, call your healthcare provider or go to the nearest hospital emergency room right away.

What are the possible side effects of ISENTRESS or ISENTRESS HD?

ISENTRESS and ISENTRESS HD can cause serious side effects including:

• Serious skin reactions and allergic reactions. Some people who take ISENTRESS or ISENTRESS HD develop serious skin reactions and allergic reactions that can be severe, and may be life-threatening or lead to death. If you develop a rash with any of the following symptoms, stop using ISENTRESS or ISENTRESS HD and call your healthcare provider right away:…

The most common side effects of ISENTRESS and ISENTRESS HD include:…

Less common side effects of ISENTRESS and ISENTRESS HD include:…

Tell your healthcare provider right away if you get unexplained muscle pain, tenderness, or weakness during treatment ISENTRESS or ISENTRESS HD…

These are not all the possible side effects of ISENTRESS and ISENTRESS HD…

How should I store ISENTRESS and ISENTRESS HD?

ISENTRESS and ISENTRESS HD film-coated tablets:

• Store ISENTRESS and ISENTRESS HD film-coated tablets at room temperature between 68°F to 77°F (20°C to 25°C)

• Store ISENTRESS and ISENTRESS HD film-coated tablets in the original package with the bottle tightly closed.

• Keep the drying agent (desiccant) in the ISENTRESS and ISENTRESS HD bottle to protect from moisture.

General information about the safe and effective use of ISENTRESS and ISENTRESS HD

…Do not use ISENTRESS or ISENTRESS HD for a condition for which it was not prescribed. Do not give ISENTRESS or ISENTRESS HD to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about ISENTRESS or ISENTRESS HD that is written for health professionals.

What are the ingredients in ISENTRESS and ISENTRESS HD?

ISENTRESS 400 mg film-coated tablets:…

ISENTRESS HD 600 mg film-coated tablets:

Active ingredient: raltegravir

Inactive ingredients: croscarmellose sodium, hypromellose 2910, magnesium stearate, microcrystalline cellulose.

The film coating contains: ferrosoferric oxide, hypromellose 2910, iron oxide yellow, lactose monohydrate, triacetin and titanium dioxide.

The tablet may also contain trace amount of carnauba wax.